Molecules of the Month

October 2023

There are three notable highlights from AbbVie this month with published details on their first-in-class PTPN2/N1 inhibitor ABBV-CLS-484, currently in Phase I trials, and their recently acquired PINK1 activator MTK458 for Parkinson’s Disease. AbbVie also released details on the development of their selective MCL-1 inhibitor ABBV-467, which had disappointingly showed signs of cardiotoxicity as seen with other MCL-1 inhibitors. Also featured this month are molecular glues currently in clinical trials from Revolution Medicines and Monte Rosa Therapeutics and a pan-KRAS degrader from Boehringer Ingelheim.

We’ll have more detailed case studies on these molecules coming soon, but in the meantime, you can check out some recent articles about the following here:

  1. RAS Inhibitor A122 - This oral tri-complex RAS(MULTI)(ON) inhibitor is a relative from a patent application of the currently undisclosed RMC-6236, which is currently in Phase I/Ib clinical trials for solid tumors. The RAS(MULTI) series was identified via SBDD based on extensive knowledge of RAS tricomplex inhibitors such as G12C tricomplex inhibitor, RMC-6291.

  2. ACBI3 - A preclinical subcutaneous pan-KRAS degrader from Boehringer Ingelheim in collaboration with Dundee’s CeTPD, was discovered from a prior KRAS inhibitor, structure-based optimization of the KRAS ligand and linkage to a VHL ligase binder.

  3. ABBV-467 - An IV, selective MCL-1 inhibitor that was terminated in Phase I clinical trials for relapsed/refractory multiple myeloma due to cardiac toxicity. AbbVie discovered the drug through an NMR-based fragment screen and structure-based design.

  4. ABBV-CLS-484 - A first-in-class, oral PTPN2/N1 active site inhibitor in Phase I clinical trials for locally advanced or metastatic tumors that was identified through structure-based drug design from thiadiazolidinone dioxide by AbbVie.

  5. FHD-286 - An oral selective allosteric BRG1/BRM ATPase inhibitor in Phase I clinical trials for metastatic uveal melanoma and in combination therapy for advanced hematologic malignancies that was discovered through a screen for BRG1/BRM inhibitors by Foghorn Therapeutics.

  6. MRT-2359 - An oral GSPT1-directed molecular glue degrader in Phase I/II clinical trials for selected cancers was identified from high-throughput screening (HTS) of a molecular glue degrader (MGD) library and AI-driven optimization by Monte Rosa Therapeutics.

  7. BMS-502 - A DGKα/ζ inhibitor in the preclinical development for PD-1 resistant tumors was discovered through an HTS and optimization by Bristol Myers Squibb.

  8. NT-0796 - An oral, selective brain-penetrant NLRP3 inflammasome inhibitor prodrug in Phase Ib/IIa clinical trials for cardiovascular risk and neuroinflammation was developed by NodThera through optimization and prodrug development from known NLRP3 inhibitor CP-456,773.

  9. PF-07202954 - An oral DGAT2 inhibitor was developed from the half-life optimization of Pfizer’s ervogastat that was discontinued in Phase I clinical trials due to the parent molecule’s clinical success.

  10. MTK458 - An oral brain-penetrant PINK1 activator intended for Parkinson’s Disease. This chemical matter helped UCSF spinout Mitokinin’s recent acquisition by AbbVie.


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