Morphic Therapeutic’s MORF-627 is an oral αvβ6 integrin inhibitor designed to treat IPF by blocking the TGFβ pathway. The Morphic team leveraged SBDD and FEP+ during lead optimization to enhance permeability and isoform selectivity. This article highlights the team’s focus on inhibiting the “bent-closed” conformation of αvβ6 as well as the linker design that led to the “chameloenicity” of the lead compound. The impressive multispecies PK and in vivo efficacy of MORF-627 in preclinical models was unfortunately accompanied by oncogenic toxicity that prevented it from reaching clinical trials.

Novartis’ HRO761 is an oral allosteric WRN helicase inhibitor, aimed at treating MSI-high and dMMR tumors. This article details the discovery of HRO761 and highlights the importance of selecting appropriate assays during early HTS as well as transferable medicinal chemistry strategies to optimize permeability and solubility through the modulation of LipE, neutral TPSA, chameleonicity, and non-classical zwitterions. It also explores the X-ray structure of HRO761 bound to WRN, how it differentiates from Vividion's VVD-214, its preclinical activity, clinical status, chemical synthesis, and more!

Revumenib (Revuforj®) is approved by the FDA as an oral, first-in-class menin-MLL interaction inhibitor for acute leukemia (AL). Since inhibition of the menin-MLL fusion protein interaction is selective for AL with a KMT2A translocation, it does not compromise normal hematopoietic function. This article covers the background, optimization and clinical development that has led to the approval of this groundbreaking new drug in a hard-to-treat indication.

HiberCell recently disclosed the discovery of HC-7366, a potential first-in-class, intentionally discovered, orally bioavailable, potent, selective, small-molecule kinase activator of GCN2. HC-7366 has now progressed to Ph. I trials to treat ccRCC and AML. This case study is a fantastic example of how to mitigate CYP3A4 inhibition and improve oral bioavailability via judicious choice of salt formulation.

Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability