Abstract 4695: Functional group elaboration of a low molecular weight fragment to yield the novel BET family bromodomain inhibitor ABBV-075

Phenotypic cell-based screening assays combined with affinity chromatography and mass-spectrometry identified the BET family of bromodomains as potential targets for blocking proliferation in a variety of cancer cell lines. Lead-finding investigations included screening a library of compounds with an average molecular weight of 225 for binding to the 13C-labeled 2nd bromodomain of BRD4 using 2-dimensional NMR. A pyridazinone fragment emerged from this effort that possessed weak binding affinity (Kd = 130 uM). The binding affinity was improved by roughly 100,000-fold through an X-ray structure enabled medicinal chemistry program that included moving to a pyrrolopyridone core along with judicious placement of additional functional groups. Antiproliferative potencies strongly correlated with potencies in a cell-based target engagement assay, suggesting that the antiproliferative effects resulted from the inhibition of BRD4/BET protein function. In vitro metabolite ID studies in rat liver microsomes helped identify sites of oxidative metabolism. The addition of fluorine atoms at these locations improved rat in vitro microsomal stability that translated to low in vivo clearance and high oral exposure in rat. The final molecule, ABBV-075, exhibited long half-lives and low unbound clearances in rat, mouse, dog and monkey. ABBV-075 demonstrated significant tumor growth inhibition in mouse flank xenograft studies representing diverse hematological and solid tumor malignancies and recently entered Phase I clinical studies. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Keith McDaniel, Le Wang, George Sheppard, Steve Fidanze, John Pratt, Dachun Liu, Lisa Hasvold, Robert Mantei, Chang Park, Aparna Sarthy, Leiming Li, Daniel H. Albert, Xiaoyu Lin, Scott Warder, Emily Faivre, Mai H. Bui, Xiaoli Huang, Denise Wilcox, Rongqi Wang, Terry Magoc, Ganesh Rajaraman, Andrew Petros, Sanjay Panchal, Chaohong Sun, Guowei Fang, Steven W. Elmore, Saul Rosenberg, Yu Shen, Warren Kati. Functional group elaboration of a low molecular weight fragment to yield the novel BET family bromodomain inhibitor ABBV-075. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4695.