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

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.针对患者的全基因组关联研究已将HSD17B13鉴定为治疗非酒精性脂肪性肝炎（NASH）及其他肝脏疾病的潜在新靶点。然而，HSD17B13的生理功能及其疾病相关底物仍未明确。此外，目前尚无针对HSD17B13的适配化学探针问世。本研究首次报道了新型强效且高选择性的HSD17B13抑制剂BI-3231的发现过程：研究以雌二醇为底物，通过高通量筛选（HTS）得到化合物1，并对其进行后续结构优化，最终获得化合物45（即BI-3231）。本研究除了对化合物45的功能、理化及药物代谢与药代动力学（DMPK）特性进行表征外，还探究了其NAD+依赖性。为支持开放科学，该HSD17B13化学探针BI-3231将通过opnMe平台向全球科研社区免费开放，以期为阐明HSD17B13的药理学特性提供助力。