Recently, a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, has emerged, including Nodthera’s ND-0796. In a push for new chemotypes, AZ and Mitsubishi Tanabe have disclosed their clinical compound, AZD4144, which is currently in Ph. I trials in healthy volunteers. The discovery story detailed their efforts to overcome PLD (phospholipidosis), genotoxicity, and hERG inhibition in a non-classical pharmacophore series. The discovery was presented by Anders Johansson at the EFMC-ISMC 2024 Meeting in Rome.

HRX-215 is an orally bioavailable MKK4 inhibitor for liver regeneration. In just over a decade since they discovered the dual specific kinase MKK4 as a master regulator of hepatocyte regeneration, HRX-215 completed a FIH clinical trial. This article is a fascinating case study on harnessing the liver's natural regenerative capacity, identifying key regulators of liver regeneration, and leveraging a kinase inhibitor with reported off-target activity for MKK4 as a suitable starting point, among other insights.

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.

As the “Guardian of the Genome,” the tumor suppressor transcription factor p53 has been a much sought-after target in oncology, with over 50% of malignancies showing mutations in p53. The p53(Y220C) mutant has been of particular interest as it creates a pocket which small molecule stabilizers are able to bind to and restore p53 function. PMV Pharma is the first to enter the clinic with their p53(Y220C) stabilizer rezatapopt, which was optimized from a hybrid of known binders and which is showing real promise against a swath of solid tumors.

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.