The pro-survival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. Using structure-based design and integrating conformational restriction as a guiding principle throughout the optimization process, we optimized a low microM HTS hit into a spiro-macrocyclic analogs series showing in vitro single digit pM inhibitory potency. Based on the hypothesis that high levels of nonbinding conformations increase the likelihood of poor selectivity and pharmacokinetic properties, we successfully used conformational restriction as a guiding principle for the optimization of these PPI inhibitors. NMR structure of a linear HTS hit series complexed with MCL1 showed a folded binding conformation, suggesting conformational restriction could be employed to form a macrocyclic ring. Combination of the conformationally restricted macrocyclic and spirocyclic rings provided high-affinity MCL1 inhibition. The X-ray crystal structure of lead macrocycle complexed with MCL1 along with molecular modeling revealed that the population of the bound conformation is approximately 10% of the total conformations accessible in solution. This provided an opportunity to further rigidize the macrocycle to obtain compounds with suitable potency and selectivity profile to serve as a tool inhibitor for characterizing the mechanism of action of MCL1 inhibition in vitro. The gain in potency was presumably due to conformational restriction, where now the observed bound conformation in complex with MCL1 was the most abundant in the unbound state. Moreover, installation of an olefin reduced the number of energetically accessible conformations within 3 kcal/mol, these analogs had short half-lives and poor oral bioavailability. Simple methylation of a secondary alcohol led to a series of compounds with improved pharmacokinetic profiles, including increased oral bioavailability. This ultimately provided AMG 176, the first selective, orally bioavailable MCL1 inhibitor to advance into human clinical trials, validating our strategy of optimization guided by conformational restriction. MCL-1 inhibitor structure complexes, along with key biophysics assays, computational chemistry rational and design process will be illustrated.

Structure-based design of potent macrocycles MCL1 inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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