Ohio University’s Chemistry and Biochemistry Colloquium Series presents “The Discovery of BET Bromodomain Inhibitor ABBV-075” with Dr. Keith McDaniel on Monday, March 27, at 4:10 p.m. in Clippinger 194.
Dr. Keith McDaniel
Abstract: Phenotypic cell-based screening assays combined with affinity chromatography and mass-spectrometry identified the BET family of bromodomains as a potential target for blocking proliferation in a variety of cancer cell lines. Screening of a small molecule fragment library for binding to the 13C-labeled 2nd bromodomain of BRD4 using 2-dimensional NMR identified a novel pyridazinone fragment (Kd = 130 µM). An X-ray structure enabled medicinal chemistry program provided a functionalized pyrrolopyridone core with roughly 100,000-fold improved binding affinity. Potencies in antiproliferative and cell-based target engagement assays correlated strongly, suggesting that antiproliferative effects resulted from the inhibition of BRD4/BET protein function. In vitro metabolite ID studies guided additional structure-activity relationship (SAR) studies that provided ABBV-075, a molecule that exhibited an excellent pharmacokinetic profile across multiple animal species. ABBV-075 demonstrated significant tumor growth inhibition in mouse flank xenograft studies representing diverse hematological and solid tumor malignancies and currently is undergoing Phase I clinical studies.
Disclosure: KFM is an employee 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.
Comments