Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties

Abstract

We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extraterminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.

Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

“… 658 JQ1 HNSCC Therapeutic targeting of BRD4 is a potent anti-cancer strategy. 659 ABBV-075 HCC Inhibit proliferation and migration of HCC 660 BET-IN-8 (Compound 27) Sepsis BET-IN-8 (2-((2-methylbenzyl) thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile) is an effective bromodomain inhibitor of BRD4 which reduces pro-inflammatory factors expression 661 BET bromodomain inhibitor 2 Not specified It is a N-Methylpyrrolidone compound which acts as a mimetic of acetyl-lysine and has enhanced affinity as inhibitor of BRD4 662 BET-IN-12 TNBC This BET-inhibitor is a triazole-containing carboline derivative (2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol) that has potent anti-tumor activity even at low doses 663 GSK1324726A (I-BET726) Neuroblastoma Selective inhibitor of BRD2, BRD3, and BRD4, which downregulates the expression of MYCN and BCL2. 664 SDR-04 Cancer cell lines It is a 3-methyl-1H-indazole derivative that is selective to BRD4 and mediates anti-proliferative activity by preventing the activation of BRD4 targets like c-MYC 665 BRD4 Inhibitor-19 U266 cancer cells It is a 3,5-dimethylisoxazole derivative that is a potent inhibitor of BRD4 666 CF53 Leukemia, Breast cancer Orally active bromodomain and extra-terminal (BET) protein inhibitor 667 BET + CBP/p300 NEO2734 NUT midline carcinoma (NMC) The Dual inhibitor of BET and CBP/p300 bromodomain imparted greater proliferation inhibition and tumor regression 522 XP-524 Pancreatic ductal adenocarcinoma XP-524 inhibited KRAS/MAPK signaling 668 CBP/p300 I-CBP112 hydrochloride ...…”

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

“…[19,20] 3 | 1,2,3-TRIAZOLE-CARBOLINE HYBRIDS The 1,2,3-triazole-carboline hybrids 5a,b (Figure 3; IC 50 : 0.6 and 0.9 nM) were potent inhibitors of bromodomain and extra-terminal (BET) and possessed excellent metabolic stability in rat, mouse, dog, monkey, and human liver microsomes with t 1/2 values in a range of 21-95 min and 19-52 min, respectively. [22,23] Further studies proved that deuteromethyl at C-4 position of 1,2,3-triazole could block oxidative metabolism. In addition, hybrid 5b demonstrated excellent pharmacokinetic properties with an oral bioavailability of 73%-100% and t 1/2 of 3.4-7.6 h in rat, mouse, dog, and monkey models.…”