Hi everyone,
I decided to change things up for this month's newsletter to include not only drug discovery literature but also FDA approvals and designations. Let me know if you would like me to continue including these by replying to this email!
Chemoproteomic discovery of a brain-penetrant, covalent NLRP3 inhibitor that binds a novel allosteric pocket
Vividion Therapeutics
https://doi.org/10.1111/bph.70626
Vividion Therapeutics have previously used their chemoproteomics platform to identify and develop clinical candidates for KEAP1 and WRN. In this work, they used their platform to identify a covalent NLRP3 inhibitor that binds to a previously unknown pocket. The initial hit had moderate potency, but was highly promiscuous. Optimisation led to potent and selective molecules which also had favourable PK properties. This allowed for in vivo proof-of-concept, where the molecule showed potent inhibition of IL-1β release in NLRP3-humanised mice. The lead molecule also showed good CNS exposure with a Kp,uu >0.5.
Phenols: From Replacing to Embracing
Gilles Ouvry
https://doi.org/10.1002/cmdc.70408
Despite being present in many important pharmaceutical drugs, phenols are often seen as a metabolic liability during drug development. In this perspective, Gilles argues that although these groups can cause issues, this should not rule out their use. He highlights several recent examples where the phenol group has been used to provide protein-ligand binding interactions, as well as for conformational control. He then compiles the clearance data for these compounds (in vitro and in vivo), showing that the majority have low-to-moderate clearance. He also noted that all but one phenol discussed are at least ortho-substituted, which could improve metabolic stability by adding steric hindrance.
Proteome-wide identification of the druggable CRBN interactome
École Polytechnique Fédérale de Lausanne, Friedrich Miescher Institute for Biomedical Research, The Barcelona Institute of Science and Technology
https://doi.org/10.1038/s41587-026-03237-7
Molecular glue discovery typically has relied on serendipity or phenotypic screening. These screens miss compounds that induce weak protein-protein binding interactions that could be optimised. In this work, the authors developed the GluePCA platform to measure binding interactions of CRBN to proteins mediated by molecular glues, primarily pomalidomide. Combining this with a computational surface-similarity search of the human proteome allowed them to identify 43 novel CRBN-pomalidomide binders. The authors expect that this workflow can be applied to other E3 ligase systems to accelerate molecular glue discovery.
FDA Approvals
A first-in-class oral RAS(ON) multi-selective tri-complex inhibitor, approved for metastatic pancreatic adenocarcinoma after roughly doubling median overall survival versus chemotherapy in RASolute 302.
Development Paper: https://doi.org/10.1021/acs.jmedchem.4c02314
The first orexin OX2 receptor agonist approved for narcolepsy type 1, and the first treatment to target the underlying orexin deficiency rather than manage symptoms downstream.
A next-generation cereblon E3 ligase modulator (CELMoD) that binds cereblon more strongly than lenalidomide, increasing IKZF1/IKZF3 degradation and retaining activity in IMiD-refractory myeloma.
Development Paper: https://doi.org/10.1021/acs.jmedchem.6b01921
The first oral drug indicated for dermatomyositis, a dual TYK2/JAK1 inhibitor targeting the interferon-driven inflammation behind the muscle and skin disease.
Development Paper: https://doi.org/10.1021/acs.jmedchem.8b00917
Fast Track and Breakthrough Therapy Designation
A brain-penetrant mutant IDH1 inhibitor granted Fast Track for IDH1-mutant glioma, where CNS exposure is the differentiator over earlier mIDH1 drugs.
A second-generation covalent KRAS G12C inhibitor with Breakthrough Therapy designation in previously treated G12C-mutant pancreatic cancer, designed for higher target occupancy than first-generation agents.
An oral covalent dual ITK/JAK3 inhibitor with Fast Track designation for moderate-to-severe lichen planus, a potentially first-in-class route to suppressing pathogenic T cells.