Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors

Journal Article · Fri Mar 24 04:00:00 EDT 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b00017· OSTI ID:1400312

Wang, Le; Pratt, John K.; Soltwedel, Todd; Sheppard, George S.; Fidanze, Steven D.; Liu, Dachun; Hasvold, Lisa A.; Mantei, Robert A.; Holms, James H.; McClellan, William J.; Wendt, Michael D.; Wada, Carol; Frey, Robin; Hansen, T. Matthew; Hubbard, Robert; Park, Chang H.; Li, Leiming; Magoc, Terrance J.; Albert, Daniel H.; Lin, Xiaoyu ; Warder, Scott E.; Kovar, Peter; Huang, Xiaoli; Wilcox, Denise; Wang, Rongqi; Rajaraman, Ganesh; Petros, Andrew M.; Hutchins, Charles W.; Panchal, Sanjay C.; Sun, Chaohong; Elmore, Steven W.; Shen, Yu; Kati, Warren M.; McDaniel, Keith F.

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. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1400312
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 9 Vol. 60; ISSN 0022-2623
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES