Dual HDAC–BRD4 inhibitors endowed with antitumor and antihyperalgesic activity

Abstract

Histone deacetylases (HDAC) are enzymes that regulate the concentration of acetylated histones which, in turns, interact with the bromodomain (BRD) of BET (Bromodomain and Extracellular domain) proteins to affect transcriptional activity. Simultaneous blockade of both epigenetic players has shown synergistic effects in a variety of cancer cell lines. In this paper we report the design, synthesis and activity of new dual inhibitors, obtained by adding a methyltriazole moiety to some HDAC inhibitors carrying a benzodiazepine core, which were previously developed by us. An Alphascreen FRET assay showed that the compounds were able to interact with BRD4-1 and BRD4-2 proteins, with some selectivity for the latter, while the HDAC inhibiting properties were measured by means of an immunoprecipitation assay. The antiproliferative activity was tested on C26 adenocarcinoma, SSMC2 melanoma and SHSY5Y neuroblastoma cells. Interestingly, both compounds were endowed with antihyperalgesic activity in the mouse Spared Nerve Injury (SNI) model.

Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization

“…The chlorinated quinoline intermediate 19 was synthesized via oxidation of quinoline 16 to the Noxide 17 with mCPBA, followed by reaction with mesyl chloride/water and subsequent chlorination with thionyl chloride to yield intermediates 18 and 19 (Scheme 3A). Suzuki-coupling of 19 and boronate 15 provided compound 20, which was then hydrolyzed and coupled to Boc-protected o-phenylenediamine 2 to yield inhibitor NB437 (22), via intermediate 21. Transmetalation of 14 with isopropyl magnesium chloride followed by reaction with dry ice provided carboxylic acid 23 (Scheme 3B).…”

“…Several dual BET/HDAC inhibitors have been developed based on BET inhibitors (+)-JQ1, 16−18 RVX-208, 19 ABBV-744, 20 I-BET295, 21 I-BET762, 22 and other inhibitor scaffolds. 23−28 As an HDAC-inhibiting moiety, most dual BET/ HDAC inhibitors are based on suberoyl anilide hydroxamic acid (SAHA), a pan-HDAC inhibitor with a relatively short metabolic half-life of 2 h. 29 These dual BET/HDAC inhibitors showed promising antitumor effects in different types of cancer cell lines, including leukemia, 19,23,25 colorectal carcinoma, 26 NUT midline carcinoma (NMC), 17,21 and PDAC cells.…”

“…Several dual BET/HDAC inhibitors have been developed based on BET inhibitors (+)-JQ1, − RVX-208, ABBV-744, I-BET295, I-BET762, and other inhibitor scaffolds. − As an HDAC-inhibiting moiety, most dual BET/HDAC inhibitors are based on suberoyl anilide hydroxamic acid (SAHA), a pan-HDAC inhibitor with a relatively short metabolic half-life of 2 h . These dual BET/HDAC inhibitors showed promising antitumor effects in different types of cancer cell lines, including leukemia, ,, colorectal carcinoma, NUT midline carcinoma (NMC), , and PDAC cells. , We have, for example, developed TW9, an adduct of the BET inhibitor (+)-JQ1 and class I HDAC inhibitor CI-994, which was more potent in inhibiting proliferation of PDAC cells than its parental molecules (+)-JQ1 or CI-994 alone, or combined treatment with both inhibitors .…”

Development of potent dual BET/HDAC inhibitorsviapharmacophore merging and structure-guided optimization

“…Several dual BET/HDAC inhibitors have been developed based on BET inhibitors (+)-JQ1 [11][12][13], RVX-208 [14], ABBV-744 [15], I-BET295 [16], I-BET762 [17], and other inhibitor scaffolds [18][19][20][21][22][23]. As an HDAC inhibiting moiety, most dual BET/HDAC inhibitors are based on suberoyl anilide hydroxamic acid (SAHA), a pan-HDAC inhibitor with a relatively short metabolic half-life of 2 h [24].…”

Targeting reader domains of the epigenetic code

“…While a number of medications, such as aspirin, reveal many of their interactions at a late stage, often including favorable off-target effects, multi-target drugs can also be intentionally designed. 226,227 Using BET inhibitors 12 228 , 13, [229][230][231] 15 232 and other scaffolds, [233][234][235][236][237][238][239][240] several inhibitors with dual BET/HDAC activity were developed in recent years. Most of these compounds are fused with HDAC inhibitor 2 by adding a simple short linker with a hydroxamic acid to the BET inhibiting moiety, resulting, among others, in compounds 16, 17 and 18 (Figure 18).…”