Molecules of the Month

April 2024

In April, Novartis disclosed their clinical YAP/TAZ-TEAD PPI inhibitor and WRN helicase inhibitor, both of which are being evaluated in Ph. I trials. Cerevel’s potential first-in-class, selective partial agonist of the D1/D5 dopamine receptors for Parkinson’s disease and Revolution Medicines’ noncovalent tri-complex molecular glue that inhibits a wide range of RAS(ON) isoforms, including KRAS, NRAS and HRAS mutants as well as wild type are also featured this month. Additional molecules we found notable from April include a heterobifunctional STAT3 degrader from Kymera Therapeutics and Tango Therapeutics’ brain penetrant PRMT5 inhibitor.

You can find out what compounds made our April 2024 Molecules of the Month list and check out recent articles for each linked below:

  1. IAG933 – A potent, selective, and first-in-class inhibitor from Novartis that directly inhibits the protein-protein interaction (PPI) between YAP/TAZ and TEAD. By blocking this PPI, IAG933 interferes with oncogenic functions downstream of the Hippo signaling pathway, particularly in mesothelioma and other tumors with NF2 loss-of-function mutations or YAP/TAZ fusions. This inhibition reduces transcriptional activity and induces cell death in cancer cells, leading to significant tumor regressions in xenograft models. Additionally, combining IAG933 preclinically with other targeted therapies (i.e., RTK, KRAS-mutant selective, and MAPK inhibitors) shows promise for improving the efficacy and durability of treatment responses. IAG933 is currently being evaluated in a Ph. I trial (NCT04857372) for solid tumors with Hippo pathway alterations. 

  2. HRO761 – A potent, selective WRN helicase inhibitor discovered by Novartis targeting cancer cells with MSI (microsatellite instability). Identified through a novel hit-finding and lead optimization approach, it binds allosterically to WRN at the interface of the D1 and D2 helicase domains, locking it in an inactive conformation. In vivo, HRO761 exhibits dose-dependent DNA damage and tumor inhibition in MSI and patient-derived xenograft models. A Ph. l trial (NCT05838768) is underway to evaluate its safety and efficacy in patients with MSI colorectal cancer and other MSI-high solid tumors.

  3. RMC-6236 – Revolution Medicine’s oral, noncovalent, tri-complex molecular glue that induces complexation between the ubiquitous intracellular chaperone, CypA (cyclophilin A), and the GTP-bound (ON) state of RAS, effectively inhibiting both the WT and a broad range of RAS(ON) isoforms, including “undruggable” mutants such as G12V/A, G13X and Q61X. In mouse preclinical xenograft models, oral administration of RMC-6236 was well tolerated and led to significant tumor regression. Preliminary clinical results from an ongoing Ph. I/Ib trial (NCT05379985) demonstrated promising objective responses in two patients with advanced KRAS G12X lung and pancreatic adenocarcinoma at a 300 mg daily dose. The most advanced clinical trial is a Ph. I/II (NCT06162221) study of RMC-6236 in combination with standard of care. The first disclosure of RMC-6236 was presented by Elena Koltun and Wei Lin in the “KRAS: Broadening the Attack Beyond G12C…” session at the AACR Annual Meeting 2024 in San Diego. 

  4. tavapadon – A potentially first-in-class, selective partial agonist of the D1/D5 dopamine receptors for the treatment of Parkinson's disease, which directly influences motor activity while minimizing side effects typical of drugs that non-selectively stimulate dopamine. In April, Cerevel shared promising topline results from its Ph. III TEMPO-3 trial (NCT04542499), which assessed tavapadon as an adjunct therapy to levodopa in Parkinson’s disease. The trial achieved its primary endpoint, demonstrating a statistically significant increase in total "on" time without troublesome dyskinesia when compared to placebo over 27 weeks (1.7 vs. 0.6 hours). In December, tavapadon became part of AbbVie's pipeline as part of its $8.7 billion acquisition of Cerevel

  5. KT-333 – A highly selective, VHL-based heterobifunctional degrader of STAT3, a transcription factor involved in various cytokine and growth factor signaling pathways, from Kymera Therapeutics. In STAT3-dependent cancers, its overactivation promotes immune suppression, tumor progression, and metastasis. This first-to-clinic transcription factor degrader has demonstrated evidence of targeted STAT3 protein degradation and pathway inhibition in humans, alongside early signs of antitumor activity. KT-333 is being evaluated in an ongoing Ph. I trial (NCT05225584) in patients with relapsed or refractory lymphomas, leukemias, and solid tumors. 

  6. TNG908 – An oral MTA-cooperative, blood-brain barrier-penetrant PRMT5 inhibitor from Tango Therapeutics. TNG908 elicited deep tumor regressions in both an MTAP-null xenograft and a subcutaneous glioblastoma multiforme (GBM) model and possesses high permeability with no major efflux liability in MDCK-MDR1 and BCRP assays. Tango’s other PRMT5 inhibitor, TNG462, has a complementary profile to TNG908, displaying significantly higher potency and selectivity for the PRMT5:MTA complex versus PRMT5, but lacking CNS exposure. A Ph. I/II study (NCT05275478) is evaluating TNG908 in homozygous MTAP-deleted cancers, including GBM.

  7. NST-628 – Nested Therapeutics’ potent, oral (pan-RAF)-MEK molecular glue that inhibits the phosphorylation and activation of MEK by blocking BRAF-CRAF heterodimer formation, offering a unique mechanism for inhibiting the RAS-MAPK signaling pathway. This approach blocks the formation of BRAF-CRAF heterodimers, a common limitation of current RAF inhibitors. NST-628 is blood-brain barrier penetrant and demonstrates broad efficacy across cell-line and patient-derived tumor models, including intracranial models with diverse MAPK pathway mutations. NST-628 is being evaluated in a Ph. I trial (NCT06326411) in adult patients with MAPK pathway mutated/dependent advanced solid tumors who have exhausted standard treatment options.

  8. CVN293 – A potent, selective, and brain-penetrant inhibitor of KCNK13 from Cerevance. KCNK13, a K+ ion channel that exhibits highly specific expression in microglia, is involved in the canonical activation of the NLRP3 inflammasome leading to neuroinflammation and is upregulated in various neurodegenerative diseases. CVN293 has been shown to reduce IL-1β production via inhibition of the NLRP3 inflammasome in LPS-primed murine microglia and is currently being evaluated in a Ph. I trial to investigate its safety, tolerability, and PK in healthy subjects. The discovery of CVN293 was presented by Andrew Stott at the 2024 Hatfield MedChem Meeting

  9. BDTX-1535 – A fourth-generation brain-penetrant TKI, discovered by Black Diamond Therapeutics, that targets a wide array of oncogenic EGFR mutations in NSCLC, including both classical and non-classical driver mutations as well as the C797S resistance mutation. This “MasterKey” inhibitor suppresses over 50 different oncogenic EGFR mutations, as demonstrated in preclinical studies. Additionally, BDTX-1535 inhibits EGFR extracellular domain mutations commonly found in GBM and avoids the paradoxical activation often seen with earlier, reversible TKIs. Ongoing clinical trials (NCT06072586 and NCT05256290) are assessing its efficacy in both GBM and NSCLC patients.

  10. sovleplenib – A potent and selective Syk inhibitor from Hutchison MediPharma discovered through optimization of a pyrido[3,4-b]pyrazine scaffold. This small molecule has a favorable preclinical PK profile and demonstrates robust anti-inflammatory efficacy in a collagen-induced arthritis model. Sovleplenib is currently in a Ph. III trial (NCT05029635) to determine its safety and efficacy in treating chronic Immune thrombocytopenic purpura. 

We thank Chris Helal (Vice President, Head of Medicinal Chemistry, Biogen, and formerly Senior Director, Medicinal Chemistry, Pfizer) for pointing out that tavapadon originated from an HTS hit and providing us a reference for Pfizer’s D1 subtype-selective agonists discovery program.


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