Ryvu Therapeutics to Present Preclinical Data on RVU120 and Synthetic Lethality Programs at the 2024 AACR Annual Meeting
- Updated preclinical data will be presented from Ryvu's synthetic lethality pipeline, including PRMT5 inhibitors in MTAP-Deficient cancers, WRN inhibitors for the treatment of microsatellite unstable (MSI-H) tumors, and Ryvu's cutting-edge synthetic lethality platform based on primary cancer cells.
- Poster presentation to highlight the synergistic effects of RVU120 in combination with ruxolitinib in myeloproliferative neoplasms.
- Ryvu's partner Menarini to present data on MEN1703 (SEL24), demonstrating promising anti-tumor activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib.
KRAKOW,
"We are excited to present our latest preclinical data at the AACR Annual Meeting, showcasing our significant progress in advancing novel small molecule therapies for oncology. This year, we will present data from our most advanced preclinical project on MTA-cooperative PRMT5 inhibitors, the lead program within Ryvu's synthetic lethality pipeline. Our PRMT5 inhibitors have demonstrated remarkable efficacy and selectivity in preclinical models of tumors with MTAP gene deletion, providing a strong foundation for further development,"
said Krzysztof Brzózka, Ph.D., Chief Scientific Officer of
Details on the poster presentations are as follows:
Abstract Title: "Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers."
Session
Poster Number: 4598
Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced, which makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors showing favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding. Structure-based lead optimization has enabled rapid expansion and delivery of two independent chemical series with novel intellectual property, characterized by high target engagement in cells, and selective potency in MTAP-deleted cell lines, along with favorable DMPK profiles allowing an oral administration. The antitumor activities were compared in vitro and in vivo in MTAP null tumors. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Performed studies confirm that MTA-cooperative PRMT5 inhibitors exert a strong synthetic lethal phenotype in MTAP-deleted cancers, offering an exciting therapeutic opportunity for a large patient population.
Abstract Title: "A comprehensive platform for identification of KRAS-specific synthetic lethal targets using patient-derived cells."
Session
Session date and time:
Ryvu's cutting-edge drug discovery platform uniquely combines high throughput capabilities with the precision and translational impact traditionally associated with later, lower throughput stages. Our approach taps into the power of primary cells to transform cancer treatment, focusing especially on colorectal cancer (CRC). By leveraging human stem cell derived model cells (PDC), patient-derived xenografts (PDXs) and clinical samples we have created a groundbreaking approach to identify synthetic lethal (SL) targets specific to oncogenic pathways. We integrate CRISPR/Cas9 technology, phenotypic screening, RNA-seq, and whole-exome sequencing (WES), enabling rapid identification of molecular vulnerabilities. We present results obtained in engineered intestinal primary models which represent frequently altered genes in CRC, including KRAS G12D mutation. Notably, our use of normal hISCs facilitates the identification of genes essential only for transformed cells, amplifying the precision tumor targeting of our novel discoveries. Beyond CRC, our platform could extend to personalized medicine approaches in various cancer types. By spearheading the identification of KRAS-specific SL inhibitors, we pave the way for novel, targeted therapies, offering hope to patients battling this heterogeneous malignancy and beyond.
Abstract Title:
"
Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors."
Session
Session date and time:
Poster Number: 5942
The synthetic lethality resulting from the inhibition of the WRN helicase protein has been observed in tumors characterized by high levels of microsatellite instability (MSI-H). This instability stems from a deficiency in the DNA mismatch repair (MMR) mechanisms, leading to the accumulation of DNA damage. This phenomenon is notably prevalent in 10-30% of colorectal, gastric, endometrial, and ovarian cancers.
Structure-based optimization performed at Ryvu facilitated the rapid expansion and delivery of a compound library with novel intellectual property (IP), demonstrating target engagement in cells and selective potency over other RecQ family members. The pharmacokinetic properties of these compounds were favorable and allowed progressing to in vivo studies which confirmed efficacy of our compounds in xenograft MSI-H cancer models. These data provide pharmacological proof-of-concept for the synthetic lethal effect of our inhibitors and support WRN inhibition as a new, targeted oncological therapy.
Abstract Title:
"Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms."
Session
Session date and time:
The presentation, prepared in collaboration with Prof. Raajit Rampal's group from
Abstract Title:
"MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as single agent and combined with ruxolitinib."
Session
Session date and time:
Poster Number: 665
MEN1703 (SEL24) is an oral, first-in-class, dual PIM/FLT3 kinase inhibitor in development for hematologic malignancies. The presented study aims to investigate the efficacy of MEN1703 alone and in combination with the JAK inhibitor ruxolitinib (RUX) in preclinical models of myelofibrosis (MF) and to elucidate the underlying signaling pathways. MEN1703 demonstrated anti-tumoral efficacy in MF preclinical models, exhibiting in vitro activity at clinically relevant concentrations. Importantly, the combination of MEN1703 with the standard of care, RUX, exhibited synergistic effects, and molecular analyses confirmed the inhibition of downstream targets of PIM. The results support the therapeutic potential and relevance of MEN1703 in the treatment strategies for myelofibrosis.
All abstracts are now available online and can be obtained from the conference site:
https://www.aacr.org/
About Ryvu Therapeutics
Ryvu's most advanced programs include RVU120, a selective CDK8/CDK19 kinase inhibitor with the potential to treat hematological malignancies and solid tumors, currently in Phase II development (i) as a monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS) as well as (ii) in combination with venetoclax for the treatment of patients with r/r AML. Another clinical program, SEL24 (MEN1703), is a dual PIM/FLT3 kinase inhibitor licensed to the
The Company was founded in 2007 and is headquartered in Kraków,
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