The utilization of structure-based design to facilitate the discovery of BCL-2 selective inhibitor Venclexta® and bromodomain and extra-terminal domain (BET) family inhibitors mivebresib and ABBV-744 will be presented. Resistance to apoptosis is a hallmark of cancer, and thus targeting pro-survival apoptotic proteins is of great interest. Using design cues from X-ray crystal structures, novel ways of accessing critical BCL-2 hotspots via rational drug design led to the discovery of Venclexta®, a potent, selective and orally active BCL-2 inhibitor that is now approved for the treatment of CLL and AML in specific patient populations. Members of the BET family of bromodomain-containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. Initiation of a fragment-based BET inhibitor project aided by X-ray structure-based design enabled the discovery of the potent, orally bioavailable pan BET inhibitor mivebresib (ABBV-075). In a follow-on effort to discover a next-generation BET inhibitor with a different biological profile relative to mivebresib, structure-based design was again employed to target BET bromodomain protein sequence differences and identify structural analogs of ABBV-075 demonstrating various levels of BET bromodomain subtype selectivity. These observations, coupled with an extensive medicinal chemistry campaign, led to the identification of BDII-selective BET inhibitor ABBV-744. Both mivebresib and ABBV-744 are currently in Phase 1 oncology clinical trials.

Use of structure-based design in the discovery of the BCL-2 selective inhibitor Venclexta® and the bromodomain and extra-terminal domain (BET) inhibitors mivebresib and ABBV-744

2019 Fall National Meeting

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