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Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.
- Source :
-
Bioorganic & Medicinal Chemistry Letters . Nov2021, Vol. 51, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
-
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]
- Subjects :
- *TRIPLE-negative breast cancer
*CANCER treatment
*CARBOLINES
*BREAST tumors
Subjects
Details
- Language :
- English
- ISSN :
- 0960894X
- Volume :
- 51
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Publication Type :
- Academic Journal
- Accession number :
- 152951178
- Full Text :
- https://doi.org/10.1016/j.bmcl.2021.128376