お知らせ • Mar 06
Ryvu Therapeutics to Present Preclinical Data on RVU120 and Synthetic Lethality Programs at the 2024 AACR Annual Meeting
Ryvu Therapeutics announced that preclinical data from its synthetic lethality pipeline and RVU120 project, as well as on MEN1703 (SEL24), will be presented at the upcoming 2024 AACR Annual Meeting, scheduled for April 5-10 in San Diego, California. 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 therapeutic opportunity for a large patient population. 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. The company 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 company have created approach to identify synthetic lethal (SL) targets specific to oncogenic pathways. The company integrate CRISPR/Cas9 technology, phenotypic screening, RNA-seq, and whole-exome sequencing (WES), enabling rapid identification of molecular vulnerabilities. The company present results obtained in engineered intestinal primary models which represent frequently altered genes in CRC, including KRAS G12D mutation. Notably, use of normal hISCs facilitates the identification of genes essential only for transformed cells, amplifying the precision tumor targeting of novel discoveries. Beyond CRC, platform could extend to personalized medicine approaches in various cancer types. By spearheading the identification of KRAS-specific SL inhibitors, The company pave the way for novel, targeted therapies, offering hope to patients battling this heterogeneous malignancy and beyond. 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 compounds in xenograft MSI-H cancer models. These data provide pharmacological proof-of-concept for the synthetic lethal effect of inhibitors and support WRN inhibition as a new, targeted oncological therapy. The presentation, prepared in collaboration with Prof. Raajit Rampal's group from Memorial Sloan Kettering Cancer Center, includes the assessment of RVU120, a highly selective and potent CDK8/19 inhibitor, both in monotherapy and combination with ruxolitinib (RUX), a JAK1/2 inhibitor, for the treatment of myeloproliferative neoplasms (MPN) and hydroxyurea-resistant/intolerant polycythemia vera (PV). The combination of RVU120 and RUX demonstrated biochemical synergy and differential inhibition of STAT5 phosphorylation in vitro. Further, in vivo treatment with RVU120/RUX+RVU120 resulted in significant reductions in disease manifestation (splenomegaly, WBC, fibrosis scoring, hematopoiesis) compared to VEH/RUX. These data suggest that JAK1/2 and CDK8/19 inhibition could be a potential novel therapeutic strategy in MPNs. Additional work on nascent RNA expression and cytokine profiles aims at elucidating the exact mechanism of synergy between tested compounds. 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.
