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!

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.

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.

BridgeBio’s acoramidis (Attruby), an oral, second-generation stabilizer of the TTR protein, has been approved by the FDA for the treatment of ATTR-CM (transthyretin amyloid cardiomyopathy). Amyloid deposits in the heart muscle characterize the rare but potentially fatal disease. This case study reviews the history of TTR modulation, early experiments validating the therapeutic potential of TTR stabilization, the binding mechanism of acoramidis to TTR, the importance of binding enthalpy for differentiation, and the molecule’s impressive 30-month clinical data following an early scare.

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.