Fig 1: (A) Inactive HSD17B13 control compound 49 (BI-0955). (B) Dose–response curves of BI-0955 (49) and BI-3231 (45) in the hHSD17B13 enzyme and cellular assays (all n = 3; SD indicated by error bars; solid lines show fitting of a four-parameter logistical equation).
Fig 2: Sequence similarities (calculated using the alignment tool in MOE36) in % between HSD17B13 and other members of the short-chain dehydrogenase/reductase (SDR) family indicate HSD17B11 as the closest homolog.
Fig 3: Synthesis of HSD17B13 Chemical Probe 45 (BI-3231)Reagents and conditions: (a) MeSO2Cl, NEt3, CH2Cl2, 90% yield; (b) N,O-bis(trimethylsilyl)acetamide, MeCN, 76% yield; (c) EtI, K2CO3, DMF, 69% yield; (d) [bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, EtOH, water, 51% yield; (e) 1-(chloromethyl)-4-methoxybenzene, K2CO3, MeCN, quant. yield; (f) n-BuLi, tetrahydrofuran (THF), -78 °C, trimethyl borate, then 4 M HCl, 91% yield; (g) trifluoroacetic acid (TFA), CH2Cl2, 69% yield.
Fig 4: Evaluation of the risk for substrate-biased hits. Percent of control values (%CTL) of a diverse set of 175 compounds assayed at 10 µM in the human HSD17B13 enzyme assay using LTB4 or estradiol as substrates (Pearson r = 0.93; linear regression (r2 = 0.87) indicated by solid line).
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