RMC-6236 is a non-covalent pan-RAS(ON) inhibitor from Revolution Medicines, which shows remarkable efficacy in tumors driven by RAS mutants that were previously considered “undruggable,” such as G12V/D/A/S, G13X, and Q61X. RMC-6236 exerts its action via a “tri-complex” mechanism, gluing RAS to the ubiquitously expressed chaperone protein, cyclophilin A. Our in-depth article covers the presentation given at the AACR 2024 meeting, which outlines the discovery and preclinical profile of RMC-6236 as well as the latest clinical updates.

Chiesi Farmaceutici’s CHF-6523 is an inhaled, lung-restricted, selective PI3Kδ inhibitor designed to provide relief to patients with COPD. Its development involved optimization of permeability and solubility as well as identification of a solid form amenable for dry powder inhalation. Disclosed at the EFMC-ISMC 2024 joint conference in Rome, Italy, this article covers the structure, development, and early clinical data of CHF-6523, which ultimately indicates that PI3Kδ inhibition may not provide clinical effect in reduction of lung inflammation.

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' NLRP3 inhibitor, NVP-DFV890, features a unique sulfonimidamide motif designed to reduce hydrolysis relative to traditional sulfonylureas. This potent compound, with promising PK in humans, is advancing through multiple clinical studies, including Ph. II trials for coronary heart disease and knee osteoarthritis. Presented by Angela Mackay at the EFMC-ISMC 2024 joint conference in Rome, this overview covers NVP-DFV890's discovery, as well as its preclinical PK and PD data.

AbbVie’s ABBV-467 is a highly potent, selective MCL-1 (myeloid cell leukemia-1) inhibitor which entered the clinic in 2022 in a Ph. I trial in patients with advanced hematologic cancers. MCL-1 has had a rough time in the clinic with multiple trials being halted or terminated due to cardiac toxicity, which is suspected to be an on-target effect. AbbVie’s approach with ABBV-467 was to target a highly potent/short half-life compound which could induce rapid apoptosis and tumor regressions in a short exposure period before the onset of any adverse events. Is this the end for MCL-1?