1. Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.
- Author
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Hill, Matthew D., Quesnelle, Claude, Tokarski, John, Fang, Haiquan, Fanslau, Carolynn, Haarhoff, Zuzana, Kramer, Melissa, Madari, Shilpa, Wiebesiek, Amy, Morrison, John, Simmermacher-Mayer, Jean, Sinz, Michael, Westhouse, Richard, Xie, Chunshan, Zhao, Jiuqiao, Huang, Lisa, Sheriff, Steven, Yan, Chunhong, Marsilio, Frank, and Everlof, Gerry
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TRIPLE-negative breast cancer , *CANCER treatment , *CARBOLINES , *BREAST tumors - Abstract
[Display omitted] We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2‐{8‐fluoro‐5‐[(3‐fluoropyridin‐2‐yl)(oxan‐4‐yl)methyl]‐7‐[4‐(2H 3)methyl‐1‐methyl‐1 H ‐1,2,3‐triazol‐5‐yl]‐5 H ‐pyrido[3,2‐b]indol‐3‐yl}propan‐2‐ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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