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 extra-terminal (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-(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 (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.

Figure 1

Representative BET inhibitors.

Figure 2

(A) LM oxidation and glucuronidation of lead series. (B) Deuteration strategy to block LM oxidation.

Scheme 1. (A) Installation of the Tz Moiety via Stille Coupling and (B) Synthetic Route to Organostannane 5(17)

Figure 3

X-ray structure of compound 15 with BRD4 (BD1). PDB code 7UZN. Close-up of the acetylated lysine binding site with omit F_o – F_c electron density contoured at 3 RMSD (blue mesh).

Figure 4

hHEP metabolic profiles of BMS-986158 (1 h incubation) and 15 (2 h incubation).