Our Research

Overview

Ryvu Therapeutics discovers and develops small molecule therapies that address high value emerging targets in oncology.

Our pipeline is built from internally-discovered candidates which make use of diverse therapeutic mechanisms, including programs directed at targets in the areas of transcriptional regulation, synthetic lethality and immuno-oncology.

Ryvu’s most advanced programs include RVU120, a selective CDK8/CDK19 kinase inhibitor with potential to treat hematological malignancies and solid tumors, currently in Phase II development for the treatment of patients with relapsed/refractory acute myeloid leukemia (r/r AML) in combination with venetoclax.

SEL24 (MEN1703) is a dual PIM/FLT3 kinase inhibitor in clinical development for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).. Additional programs include synthetic lethality candidates directed at WRN and MTAP deletions as well as immuno-oncology programs focused on STING agonists and HPK1.

  • Clinical Projects
  • Immuno-oncology Collaborations
  • Synthetic Lethality

OUR
RESEARCH

RVU120 SEL24
(MEN1703) IO WRN PRMT5

Clinical Projects

  • RVU120

    CDK8 is a kinase submodule of the mediator complex, involved in both transcriptional activation and repression. CDK8- mediator complex integrates basal transcriptional machinery with the activity of oncogenic transcriptional and epigenetic factors. Targeting CDK8 and...

  • MEN1703 (SEL24)

    MEN1703 (SEL24) is a selective, dual inhibitor of PIM and FLT3 kinases, two enzymes that are strongly implicated in malignant transformation of hematopoietic cells. The compound is a novel small molecule discovered by Ryvu, and...

Top Belt

RVU120

CDK8 is a kinase submodule of the mediator complex, involved in both transcriptional activation and repression. CDK8- mediator complex integrates basal transcriptional machinery with the activity of oncogenic transcriptional and epigenetic factors. Targeting CDK8 and its paralog CDK19 using potent and selective CDK8 inhibitor RVU120 may be an effective way for treatment of both hematological malignancies and solid tumors with deregulated transcription.  Functional studies defined CDK8 as a regulator of paracrine activities of cancer cells, hypoxia response network and other pathways including the p53 network, the Wnt–β-catenin pathway, the Notch1,  JAK/STAT1 signaling, and pathways regulated by SMAD TFs. Because of the established role in repression of NK cell cytotoxicity and tumor surveillance, CDK8 inhibitors may also have utility as an immunooncology treatment.

In March 2019 Ryvu received approval from the U.S. Food and Drug Administration to initiate a Phase 1b study for its RVU120 program in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (HR-MDS) and first patient was dosed in September 2019. On March 25, 2020, the U.S. Food and Drug Administration (FDA) granted an orphan drug designation (ODD) to RVU120, for the treatment of patients with acute myeloid leukemia (AML).

The first data from the program, comprising the first five evaluable patients, presented at EHA 2021 conference, demonstrated favorable safety profile and initial single agent activity (complete response in AML and erythroid response in MDS).

In addition, RVU120 has demonstrated single agent efficacy in multiple solid tumor models. On August 25, 2021, the first patient enrolled in the Phase I/II clinical trial investigating RVU120 (SEL120) in relapsed/refractory metastatic or advanced solid tumors, has received the first dose of the study drug.

KEY FACTS:

  • RVU120 is a selective CDK8/CDK19 inhibitor in Phase I in patients with AML/ HR-MDS (NCT04021368), and Phase I/II in relapsed/refractory metastatic or advanced solid tumors
  • RVU120 treatment results in on-target efficacy in preclinical models of AML in vitro and in vivo
  • Inhibition of CDK8 can repress key oncogenic transcriptional programs and induce lineage commitment genes in AML
  • CDK8 and CDK19 are also preclinically validated novel targets for the treatment of breast and prostate cancers
  • There are no competitive CDK8/19 inhibitors actively tested in clinical trials

RYVU’s APPROACH:

  • RVU120 is a clinical stage highly specific and orally bioavailable dual CDK8/CDK19 inhibitor
  • First patient dosed in Phase Ib trial in AML and HR-MDS in August 2019
  • First patient dosed in Phase i/II trial in solid tumors in August 2021
  • First Patient dosed in the RIVER-81 Phase II study of RVU120 in combination with venetoclax in January 2024
  • Demonstrated high on-target efficacy, including complete regressions in preclinical models of AML
  • Efficacy in leukemia cells linked with induction of apoptotic cell death and induction of differentiation
  • Demonstrated synergy with standard of care and late stage development candidate drugs in AML
  • Specific inhibition of CDK8/19 biomarkers correlates with efficacy in responder cells in the low nM range
  • On-target transcriptional changes in cancer cells with RVU120, including inhibition of oncogenic gene expression patterns and induction of lineage commitment genes
  • Bioinformatic analysis of treated cells allowed for in-depth understanding of a link between molecular mode of action and response in cancer cells
  • Differential efficacy of RVU120 demonstrated also in breast cancer, Willms tumors, Lymphomas and colorectal cancer models in vitro and in vivo
  • Synergy of RVU120 with anti-PD1 antibodies in immunooncology in vivo models
  • RVU120 treatment effectively increases reticulocyte and hemoglobin levels in models of a rare ribosomopathy – Diamond-Blackfan Anemia
  • Partnership with The Leukemia & Lymphoma Society to co-fund and scientifically support further preclinical and clinical development of RVU120

  • JANUARY 2024

    First Patient dosed in the RIVER-81 Phase II study of RVU120 in combination with venetoclax.

  • JUNE 2023

    Manageable safety profile and promising evidence of anti-leukemic activity of RVU120 monotherapy in AML and HR-MDS patients, presented at the EHA 2023 conference. Moreover, the preclinical data of RVU120 in combination with the JAK1/2 inhibitor ruxolitinib (RUX) in myeloproliferative neoplasms was demonstrated.

  • DECEMBER 2022

    Single-agent activity of RVU120 with a complete response, 4 blast reductions, and 4 erythroid and/or platelet responses in patients with r/r AML or HR-MDS, presented at the ASH 2022 conference.

  • OCTOBER 2022

    Updated data from Phase I/II dose-escalation study of RVU120 with 4 disease stabilizations in advanced solid tumor patients, released at the ENA 2022 conference.

  • JUNE 2022

    Clinically meaningful benefit of RVU120 monotherapy: a complete remission in an AML patient with FLT3/DNMT3A/NPM1 mutations; more than 18-month duration of therapy in a DNMT3A-mutated high-risk MDS patient; stable diseases with blast reductions in 3 additional patients, demonstrated at the EHA 2022 Congress.

  • DECEMBER 2021

    Single-agent activity of RVU120 (complete response in r/r AML and erythroid response in HR-MDS), as well as an acceptable safety profile in 6 patients with no dose-limiting toxicity or treatment-related SAEs, presented at the ASH 2022 conference.

  • AUGUST 2021

    First patient dosed in Phase I/II study in patients with relapsed/refractory metastatic or advanced solid tumors.

  • JUNE 2021

    The first data from the program, comprising the first five evaluable patients, presented at EHA 2021 conference, demonstrated favorable safety profile and initial single agent activity (complete response in AML and erythroid response in MDS).

  • MAY 2021

    Ryvu’s Clinical Trial Application (CTA) to commence a single-agent, open-label Phase I/II trial, investigating the safety and efficacy of RVU120 (SEL120) in patients with relapsed/refractory metastatic or advanced solid tumors, was approved by the Polish Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, and the respective Central Ethics Committee.

  • MARCH 2020

    Ryvu received Orphan Drug Designation from FDA for RVU120 to treat Acute Myeloid Leukemia.

  • SEPTEMBER 2019

    First patient dosed in Phase 1b trial in AML and HR-MDS patients.

  • MARCH 2019

    Ryvu received approval from the U.S. Food and Drug Administration to initiate a Phase 1b study for its RVU120 program in acute myeloid leukemia and high-risk myelodysplastic syndromes.

  • AUGUST 2017

    Ryvu has initiated a partnership with The Leukemia & Lymphoma Society to co-fund and scientifically support further preclinical and clinical development of RVU120 as a targeted therapy to treat patients with acute myeloid leukemia.

Ryvu poster publications:

AACR-NCI-EORTC International Conference (ENA) 2024, October 23-25, 2024

  • Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors

    PDF Download

European Hematology Association (EHA) Congress, June 13 -16, 2024

  • RVU120, a first-in-class CDK8 inhibitor for the treatment of relapsed/refractory AML and high-risk MDS: preliminary results from two ongoing studies.

    PDF Download

  • Synergistic potential of RVU120, a first-in-class CDK8/CDK19 inhibitor, with venetoclax in AML: preclinical and initial clinical insights.

    PDF Download

  • CDK8/19 Inhibition: A Promising Therapeutic Strategy in Myeloproliferative Neoplasms.

    PDF Download

American Association for Cancer Research (AACR) Annual Meeting, April 5-10, 2024

  • Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms.

    PDF Download
See More

RECOMMENDED LITERATURE:

REVIEW ARTICLES

  • Philip, Stephen, Malika Kumarasiri, Theodosia Teo, Mingfeng Yu, and Shudong Wang, ‘Cyclin-Dependent Kinase 8: A New Hope in Targeted Cancer Therapy?’, Journal of Medicinal Chemistry, 2017, acs.jmedchem.7b00901 https://doi.org/10.1021/acs.jmedchem.7b00901
  • Roninson, Igor B., Balázs Győrffy, Zachary T. Mack, Alexander A. Shtil, Michael S. Shtutman, Mengqian Chen, and others, ‘Identifying Cancers Impacted by CDK8/19’, Cells, 8 (2019), 821 https://doi.org/10.3390/cells8080821
  • Rzymski, Tomasz, Michał Mikula, Katarzyna Wiklik, and Krzysztof Brzózka, ‘CDK8 Kinase–An Emerging Target in Targeted Cancer Therapy.’, Biochimica et Biophysica Acta, 1854 (2015), 1617–29 https://doi.org/10.1016/j.bbapap.2015.05.011

SCIENTIFIC PAPERS

  • Rzymski, Tomasz, Michał Mikula, Eliza Żyłkiewicz, Agnieszka Dreas, Katarzyna Wiklik, Aniela Gołas, and others, ‘SEL120-34A Is a Novel CDK8 Inhibitor Active in AML Cells with High Levels of Serine Phosphorylation of STAT1 and STAT5 Transactivation Domains’, Oncotarget, 8 (2017), 33779–95 https://doi.org/10.18632/oncotarget.16810
  • Nitulescu, Ioana I., Sara C. Meyer, Qiang Jeremy Wen, John D. Crispino, Madeleine E. Lemieux, Ross L. Levine, and others, ‘Mediator Kinase Phosphorylation of STAT1 S727 Promotes Growth of Neoplasms With JAK-STAT Activation’, EBioMedicine, 26 (2017), 112–25 https://doi.org/10.1016/j.ebiom.2017.11.013
  • Pelish, Henry E, Brian B Liau, Ioana I Nitulescu, Anupong Tangpeerachaikul, Zachary C Poss, Diogo H Da Silva, and others, ‘Mediator Kinase Inhibition Further Activates Super-Enhancer-Associated Genes in AML.’, Nature, 2015 https://doi.org/10.1038/nature14904
  • Xu, Dazhi, Chien-Feng Li, Xian Zhang, Zhaohui Gong, Chia-Hsin Chan, Szu-Wei Lee, and others, ‘Skp2-MacroH2A1-CDK8 Axis Orchestrates G2/M Transition and Tumorigenesis.’, Nature Communications, 6 (2015), 6641 https://doi.org/10.1038/ncomms7641
  • McDermott, Martina S.J., Alexander A. Chumanevich, Chang Uk Lim, Jiaxin Liang, Mengqian Chen, Serena Altilia, and others, ‘Inhibition of CDK8 Mediator Kinase Suppresses Estrogen Dependent Transcription and the Growth of Estrogen Receptor Positive Breast Cancer’, Oncotarget, 8 (2017), 12558–75 https://doi.org/10.18632/oncotarget.14894
  • Hsieh, Robert W, Angera H Kuo, Ferenc A Scheeren, Mark A Zarnegar, Shaheen S Sikandar, Jane Antony, and others, ‘CDK19 Is a Regulator of Triple-Negative Breast Cancer Growth’, BioRxiv, 2018 https://doi.org/https://doi.org/10.1101/317776
  • Bra Gelmann, J., N. Klu mper, Anne Offermann, A. von Ma senhausen, D. Bohm, M. Deng, and others, ‘Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer’, Clinical Cancer Research, 2016 https://doi.org/10.1158/1078-0432.CCR-16-0094
  • Witalisz-Siepracka, Agnieszka, Dagmar Gotthardt, Michaela Prchal-Murphy, Zrinka Didara, Ingeborg Menzl, Daniela Prinz, and others, ‘NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses’, Cancer Immunology Research, 2018, canimm.0183.2017 https://doi.org/10.1158/2326-6066.CIR-17-0183

FOR PATIENTS

Clinical Trials
  • disease
  • intervention
  • study
  • title
  • status
  • learn more
  • AML
  • RVU120
  • CLI 120
  • A Phase Ib Study of RVU120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome
  • Recruitment closed
  • About trial
  • Solid Tumors
  • RVU120
  • AMNYS-51
  • An Open-label, Single Agent, Phase I/II Trial Investigating the Safety and Efficacy of RVU120 (SEL120) in Patients With Relapse / Refractory Metastatic or Advanced Solid Tumors
  • Recruiting
  • About trial
  • AML/HR-MDS
  • RVU120
  • RIVER-52
  • A Multicenter, Open-Label Clinical Trial of RVU120 in Patients With Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia With or Without NPM1 Mutation (RIVER-52)
  • Recruiting
  • About trial
  • AML/HR-MDS
  • RVU120 + venetoclax
  • RIVER-81
  • A Multicenter, Open-Label, Dose-Finding Clinical Trial to Assess the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Efficacy of RVU120 in Combination With Venetoclax in Participants With Acute Myeloid Leukemia Who Failed Prior Therapy With Ventoclax and a Hypomethylating Agent (RIVER-81)
  • Recruiting
  • About trial
Bottom Belt
Top Belt

MEN1703 (SEL24)

MEN1703 (SEL24) is a selective, dual inhibitor of PIM and FLT3 kinases, two enzymes that are strongly implicated in malignant transformation of hematopoietic cells. The compound is a novel small molecule discovered by Ryvu, and licensed to the Menarini Group in 2017. Menarini has global rights for further development of the compound and is a sole sponsor of the study.

MEN1703 (SEL24) was initially developed in the area of acute myeloid leukemia (AML).

In September 2023, Ryvu announced that its licensee, the Menarini Group, will expand development of MEN1703 (SEL24) by initiating a new Phase II study in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in addition to continued translational work in other hematologic indications.

The Phase II study, which will explore the activity of MEN1703 in combination with standard-of-care therapy in DLBCL and as a single agent, is being initiated based on strong preclinical activity of MEN1703 in lymphoma. MEN1703 has completed Phase II studies in relapsed/refractory AML, including an expansion cohort in IDH-mutated AML. The studies demonstrated an acceptable safety profile and early signs of single agent activity. Based on these data, development of MEN1703 will continue with focus on DLBCL and potentially other indications. AML will be deprioritized given the existing data and competitive landscape.

Ryvu will become an operational partner as part of an amended agreement, enabling Ryvu to execute clinical studies on behalf of Menarini. Menarini will continue to be responsible for all research and development costs.

KEY FACTS:

  • SEL24 is a selective, orally bioavailable dual PIM/FLT3 inhibitor with successfully completed Phase I trial in patients with AML (NCT03008187)
  • PIM and FLT3 are oncogenes involved in AML
  • Dual targeting creates potential for broader activity and more durable responses than selective FLT3 inhibitors
  • Potential for treating patients that have relapsed on selective FLT3 inhibitors – PIM kinases are largely responsible for the development of resistance to FLT3 inhibitors
  • PIM kinases are also involved in other types of different malignancies, including lymphomas and solid tumors
  • Project was developed by Ryvu up to initiation of phase I clinical studies in 2017, with first patient dosed in the study in March 2017
  • Phase I dose escalation study was successfully completed with the establishment of the recommended dose for Phase II studies of the drug in March 2020
  • FDA granted an orphan drug designation (ODD) to MEN1703 (SEL24) for the treatment of patients with AML
  • Partnered globally with Menarini in 2017
  • Menarini plans to continue the study in Phase II (cohort expansion) at the recommended dose level
  • Ryvu will execute clinical studies on behalf of Menarini in advanced DLBCL

  • SEPTEMBER 2023

    Expansion of development of MEN1703 (SEL24) by initiating a new Phase II study in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

  • JUNE 2022

    Promising efficacy of MEN1703 (SEL24) from an additional expansion cohort in the IDHm AML patients, reported at the EHA 2022 Congress.

  • DECEMBER 2021

    Updated Phase 2 data for MEN1703 (SEL24), showing pharmacodynamics (PD) and genomic profiling in the First-in-Human Diamond-01 trial, demonstrated at the ASH 2022 conference.

  • NOVEMBER 2021

    Orphan Drug Designation from FDA for MEN1703 (SEL24) to treat Acute Myeloid Leukemia.

  • JUNE 2022

    Promising efficacy of MEN1703 (SEL24) from an additional expansion cohort in the IDHm AML patients, reported at the EHA 2021 Congress.

  • SEPTEMBER 2020

    First patient dosed in Europe within the Expansion Cohort of Phase I/II Clinical Study of SEL24/MEN1703 in Acute Myeloid Leukemia.

  • MARCH 2020

    Successful Completion of Phase I Clinical Study of SEL24/MEN1703 in Acute Myeloid Leukemia.

  • MARCH 2017

    Selvita and Menarini Group announce global license agreement for SEL24.

Ryvu poster publications:

American Association for Cancer Research (AACR) Annual Meeting, April 5-10, 2024

  • MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib.

    PDF Download

AACR-NCI-EORTC International Conference (ENA) 2023, October 11-15, 2023

  • MEN1703/SEL24, A Potent PIM Inhibitor, Demonstrates Promising Anti-Tumor Activity in Activated B Cell Like DLBCL, Mantle Cell Lymphoma and Marginal Zone Lymphoma Cells

    PDF Download

American Society of Hematology (ASH) Annual Meeting, December 10 –13, 2022

  • PIM Inhibition by SEL24 (MEN1703) Combines Synergistically with gilteritinib in FLT3-ITD Preclinical Models of Acute Myeloid Leukemia

    PDF Download

  • Super-enhancer-driven PIM Kinase Upregulation in Multiple Myeloma Maintains the Plasma Cell-specific Oncogenic and Microenvironmental Circuits and Can Be Efficiently Targeted by the Pan-PIM Inhibitor MEN1703

    PDF Download

  • PIM Kinases Regulate Super-Enhancer-Dependent Gene Expression In Diffuse Large B-Cell Lymphoma

    PDF Download

  • MEN1703-mediated PIM kinases inhibition impairs protumoral and immunosuppressive phenotype and functions of macrophages in classical Hodgkin Lymphoma

    PDF Download
See More

RECOMMENDED LITERATURE:

REVIEW ARTICLES:

  • PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer Published: 31 January 2020, Sabina Luszczak, Christopher Kumar, Vignesh Krishna Sathyadevan, Benjamin S. Simpson, Kathy A. Gately, Hayley C. Whitaker & Susan Heavey
    Signal Transduction and Targeted Therapy volume 5, Article number: 7 (2020)
    https://www.nature.com/articles/s41392-020-0109-y
  • J Cancer Prev. 2018 Sep; 23(3): 109–116. doi: 10.15430/JCP.2018.23.3.109
    PIM Kinase as an Executional Target in Cancer
    Xinning Zhang, Mengqiu Song, Joydeb Kumar Kundu, Mee-Hyun Lee and Zhen-Zhen Liu
  • Bioinformation. 2019; 15(1): 40–45. doi: 10.6026/97320630015040
    A review on PIM kinases in tumors. Housna Arrouchi,1 Wiame Lakhlili,1,* and Azeddine Ibrahimi1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651028
  • Science Advances 18 Sep 2015: Vol. 1, no. 8, e1500221; DOI: 10.1126/sciadv.1500221
    Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia
    Alexa S. Green, Thiago T. Maciel, Marie-Anne Hospital, Chae Yin, Fetta Mazed, Elizabeth C. Townsend1, Sylvain Pilorge, Mireille Lambert, Etienne Paubelle, Arnaud Jacquel, Florence Zylbersztejn, Justine Decroocq, Laury Poulain, Pierre Sujobert, Nathalie Jacque, Kevin Adam, Jason C. C. So, Olivier Kosmider , Patrick Auberger, Olivier Hermine, David M. Weinstock1, Catherine Lacombe, Patrick Mayeux, Gary J. Vanasse, Anskar Y. Leung, Ivan C. Moura,†, Didier Bouscary,† and Jerome Tamburini,†,‡
  • Leukemia volume 34, pages682–696(2020) FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Ahmad I. Antar, Zaher K. Otrock, Elias Jabbour, Mohamad Mohty & Ali Bazarbachi. https://www.nature.com/articles/s41375-019-0694-3
  • Journal of Hematology & Oncology volume 11, Article number: 133 (2018) FLT3 inhibitors in acute myeloid leukemia. Mei Wu, Chuntuan Li & Xiongpeng Zhu.
    https://jhoonline.biomedcentral.com/articles/10.1186/s13045-018-0675-4

SCIENTIFIC PAPERS:

  • Oncotarget. 2018 Mar 30; 9(24): 16917–16931. doi: 10.18632/oncotarget.24747
    A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia
    Wojciech Czardybon, Renata Windak, Aniela Gołas, Michał Gałęzowski, Aleksandra Sabiniarz, Izabela Dolata, Magdalena Salwińska, Paweł Guzik, Magdalena Zawadzka, Ewelina Gabor-Worwa, Bożena Winnik, Małgorzata Żurawska, Ewa Kolasińska, Ewelina Wincza, Marta Bugaj, Monika Danielewicz, Eliza Majewska, Milena Mazan, Grzegorz Dubin, Monika Noyszewska-Kania, Ewa Jabłońska, Maciej Szydłowski, Tomasz Sewastianik, Bartosz Puła, Anna Szumera-Ciećkiewicz, Monika Prochorec-Sobieszek, Elżbieta Mądro, Ewa Lech-Marańda, Krzysztof Warzocha, Jerome Tamburini, Przemysław Juszczyński, and Krzysztof Brzózka
  • J Cell Mol Med. 2018 Jul;22(7):3548-3559 Microenvironment-induced PIM kinases promote CXCR4-triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration.
    Białopiotrowicz E, Górniak P, Noyszewska-Kania M, Puła B, Makuch-Łasica H, Nowak G, Bluszcz A, Szydłowski M, Jabłonska E, Piechna K, Sewastianik T, Polak A, Lech-Marańda E, Budziszewska BK, Wasylecka-Juszczyńska M, Borg K, Warzocha K, Czardybon W, Gałęzowski M, Windak R, Brzózka K, Juszczyński P.
  • Blood. 2017 Sep 21;130(12):1418-1429 Expression of PIM kinases in Reed-Sternberg cells fosters immune privilege and tumor cell survival in Hodgkin lymphoma
    Szydłowski M, Prochorec-Sobieszek M, Szumera-Ciećkiewicz A, Derezińska E, Hoser G, Wasilewska D, Szymańska-Giemza O, Jabłońska E, Białopiotrowicz E, Sewastianik T, Polak A, Czardybon W, Gałęzowski M, Windak R, Zaucha JM, Warzocha K, Brzózka K, Juszczyński P.

Clinical Trials
  • disease
  • intervention
  • study
  • title
  • status
  • learn more
  • Acute Myeloid Leukemia
  • SEL24 (MEN1703)
  • Menarini Group
  • A Phase I/II Study of SEL24 in Patients With Acute Myeloid Leukemia
  • Recruiting
  • clinicaltrials.gov
Bottom Belt

Synthetic Lethality

One of the challenges in the development of new oncology therapeutics is the limited number of protein targets known to be addressable with small molecules. Synthetic lethality allows the identification of novel protein targets and mechanisms of cancer cell sensitivity that can be used therapeutically.

Compounds active on specific synthetic lethal targets selectively kill tumor cells of a precisely defined model system, characterized by a specific genetic, epigenetic or metabolic characteristic. This is the approach actively investigated at Ryvu that allows the generation of compounds with highly specific and well-characterized activity.

  • MTA-COOPERATIVE PRMT5 INHIBITOR

    Deletion of 9p21 locus is one of the most frequent genetic alterations associated with human cancers. Apart from tumour suppressor CDKN2A, locus 9p21 contains the gene coding methylthioadenosine phosphorylase (MTAP), the only enzyme capable of...

  • WRN INHIBITOR

    Werner Syndrome helicase (WRN) is a member of the RecQ helicase family and plays an important role in controlling DNA repair mechanisms and maintaining integrity of the genome. WRN helicase has been identified to be...

Top Belt

MTA-COOPERATIVE PRMT5 INHIBITOR

Deletion of 9p21 locus is one of the most frequent genetic alterations associated with human cancers. Apart from tumour suppressor CDKN2A, locus 9p21 contains the gene coding methylthioadenosine phosphorylase (MTAP), the only enzyme capable of degrading methylthioadenosine (MTA). Accumulation of MTA in cells with MTAP deletion causes a partial inhibition of the methylation activity of PRMT5 (protein arginine methyl transferase 5), which is not the case in healthy cells. MTA-bound PRMT5 makes cancer cells vulnerable to further inhibition of its activity by small molecule drugs, which leads to cell death. Thus PRMT5-MTA complex forms a novel synthetic lethal target for treatment of MTAP-deleted tumors and gives hope for creating a targeted therapy for a huge population of cancer patients (up to 15%).

 

KEY FACTS:

  • Co-deletion of MTAP may be observed in 80-90% of all tumors harboring homozygous deletion of CDKN2A, which represents 10-15% of all human tumors.
  • Many of these tumor types, such as non-small cell lung cancer, pancreatic cancer or glioblastoma (GBM) are associated with poor prognosis, representing a significant unmet medical need.

 

MECHANISM OF ACTION

RYVU STRATEGY:

  • Small molecule, MTA-cooperative PRMT5 inhibitors, targeting cells with MTAP deletion
  • Compounds selectively inhibit viability of MTAP deleted cancer cells, while not affecting healthy cells

 

RECOMMENDED LITERATURE:

Mavrakis et al., Disordered methionine metabolism in MTAPCDKN2A deleted cancers leads to dependence on PRMT5. Science. 2016 Mar 11;351(6278):1208-13. doi: 10.1126/science.aad5944.

Kryukov et al., MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214.

Marjon et al., MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell Rep. 2016 Apr 19;15(3):574-587. doi: 10.1016/j.celrep.2016.03.043.

Bottom Belt
Top Belt

WRN INHIBITOR

Werner Syndrome helicase (WRN) is a member of the RecQ helicase family and plays an important role in controlling DNA repair mechanisms and maintaining integrity of the genome. WRN helicase has been identified to be indispensable in tumor cells with microsatellite instability (MSI), where inhibition of the protein’s helicase/ATPase activity leads to impairment of cellular viability. This therapeutic strategy based on synthetic lethality allows to selectively kill MSI tumor cells, and holds promise for patients with MSI tumors across multiple indications, such as colorectal, ovarian, endometrial and gastric cancers.

 

KEY FACTS

  1. WRN is critical for cellular viability in MSI tumor cells

 

RYVU STRATEGY

  1. Potent small-molecule inhibitors selectively inhibiting WRN’s helicase/ATPase activity
  2. First- or best-in-class potential

 

RECOMMENDED LITERATURE:

Chan EM et al. WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers (2019) 568:551–556, Nature

Lieb S et al. Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells (2019) 8:e43333, eLife

 

 

 

Bottom Belt

Novel Targets

Beyond publicly disclosed programs, Ryvu is working on candidates that address novel targets in the areas of synthetic lethality, immuno-oncology and immunometabolism to generate new therapeutics with first-in-class or best-in-class potential.

For the candidates, Ryvu is utilizing a proprietary drug discovery approach combining internally developed expertise and new sophisticated tools and technologies to identify small molecule compounds with favorable profiles and activity.

Immuno-Oncology and other R&D Collaborations

In November 2022, Ryvu Therapeutics and BioNTech have entered into a multi-target research collaboration for several small molecule immunotherapy programs. BioNTech and Ryvu will jointly undertake drug discovery and research projects to develop multiple small molecule programs directed at exclusive targets selected by BioNTech, primarily focused on immune modulation within oncology, with potential applications in other disease areas.

In 2013, Ryvu and Merck KGaA initiated a joint research strategy involving intensive work on multiple targets and several chemical series. The collaboration has successfully completed two milestones and has been expanded over time with additional targets.
The aim of the partnership with Merck is the development of new anticancer therapeutics acting on diverse biological targets associated with aberrant metabolic pathways in cancer cells. Dependence on specific metabolic pathways is a feature of various types of cancer, therefore, targeting this vulnerability has many potential applications in a broad range of patient populations.
The collaboration has resulted in scientific achievements, the joint filing of patent applications and data presentations at international scientific conferences.

In 2022 Ryvu and Exelixis signed an exclusive license agreement focused on the development of novel targeted therapies utilizing Ryvu’s STING (STimulator of INterferon Genes) technology. The agreement expands Exelixis’ portfolio of biotherapeutics by combining Ryvu’s proprietary small molecule STING agonists and STING biology know-how with Exelixis’ network of expertise and resources in antibody engineering, antibody-drug conjugate (ADC) technologies, and proven history of developing and commercializing oncology therapeutics.

Publications

AACR-NCI-EORTC International Conference (ENA) 2024, October 23-25, 2024

  • Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors

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  • Discovery of novel MTA-cooperative PRMT5 preclinical candidate as targeted therapeutics for MTAP-deleted cancers

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  • Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors

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  • Exploring Synthetic Lethality and Novel Drug Combinations in Patient-Derived Cells

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European Hematology Association (EHA) Congress, June 13 -16, 2024

  • RVU120, a first-in-class CDK8 inhibitor for the treatment of relapsed/refractory AML and high-risk MDS: preliminary results from two ongoing studies.

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  • Synergistic potential of RVU120, a first-in-class CDK8/CDK19 inhibitor, with venetoclax in AML: preclinical and initial clinical insights.

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  • CDK8/19 Inhibition: A Promising Therapeutic Strategy in Myeloproliferative Neoplasms.

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American Association for Cancer Research (AACR) Annual Meeting, April 5-10, 2024

  • Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers

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  • Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors

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  • A Comprehensive Platform for Identification of KRAS-specific Synthetic Lethal Targets using Patient-Derived Cells

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  • MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib.

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  • Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms.

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American Society of Hematology (ASH) Annual Meeting, December 9 –12, 2023

  • Safety and Efficacy Results from CLI120-001 a Phase 1 Study in RR-AML and HRMDS: Update from Higher Dose Levels

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  • Preclinical and Clinical Evidence for Erythroid-Stimulating Activity of RVU120 CDK8/19 Inhibitor in AML and MDS

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  • Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relieves Differentiation Block in MDS/AML

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  • Targeting CDK8/CDK19 to Disrupt Leukemic Stem Cell-like Population in Acute Myeloid Leukemia: Exploring RVU120 As a Promising Frontline Therapy

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  • Mediator Kinase/CDK8 Inhibition as a Strategy to Improve FLT3 Inhibitor Activity in Acute Myeloid Leukemia

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