Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

Abstract

Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD + dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.

Phenyl dialkynylcarbinols, a Bioinspired Series of Synthetic Antitumor Acetylenic Lipids

“…As a proof of concept (POC), this simple readout was used here to characterize the recently developed HSD17B13 selective inhibitor BI-3231. 44 These POC data support the notion that PACs represent valuable probes to identify and characterize inhibitors of HSD17B11 and HSD17B13 and evaluate their selectivity. Genome-wide association studies identified HSD17B13 as an attractive therapeutic target in the context of non-alcoholic fatty liver disease, 57 and our approach opens up the prospects of simplifying the screen for novel selective HSD17B13 inhibitors.…”

“…When incubated with cells at 1 μM for 72 h, the PAC ( S )- 5.8a reduces the cellular viability of U2OS KO HSD17B11 complemented by HSD17B11 or HSD17B13 down to ≈0%, while it has only a small effect on the control cells (GFP complemented, 90–92% viability). In these conditions, we used the recently described selective HSD17B13 inhibitor BI-3231 available thanks to the opnMe platform, to establish at which concentration it was able to inhibit the HSD17B11 and HSD17B13-dependent ( S )- 5.8a cytotoxic activity (Figure A,B). Computing from the measured viability the % of HSD17B11 or HSD17B13 bioactivating activity at increasing inhibitor concentrations led us to establish in U2OS a cellular IC 50 of 117 nM for BI-3231 against HSD17B13 and of >10 μM against HSD17B11.…”

“…The bioactivation of some PACs by both HSD17B11 and HSD17B13 represents a valuable tool to translate the cellular catalytic activity of these enzymes into cytotoxicity which is easy to monitor. As a proof of concept (POC), this simple readout was used here to characterize the recently developed HSD17B13 selective inhibitor BI-3231 . These POC data support the notion that PACs represent valuable probes to identify and characterize inhibitors of HSD17B11 and HSD17B13 and evaluate their selectivity.…”

Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13

“…Of note, a phenol-containing compound, BI-3231, was recently reported to be a potent and selective human HSD17B13 inhibitor 44 . We docked BI-3231 into the active site of HSD17B13/ 1 complex structure (Supplementary Figure 6 ).…”

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

“…Recent pilot high-throughput screen has identified BI-3231, the small molecule that displays extremely high potency against human HSD17β13 (IC 50 = 1 nM, Ki = 0.7 nM, Fig. 5 B) and the majority of BI-3231 is enriched in liver with optimal pharmacokinetic properties [ 170 ].…”