基于 2-羟基吡唑并[1,5-a]嘧啶骨架的高效人二氢乳清酸脱氢酶抑制剂靶向治疗急性髓系白血病：联苯部分的 SAR。

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-]pyridine Scaffold: SAR of the Biphenyl Moiety.

机构信息

Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Turin 10125, Italy.

Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, Turin 10043, Italy.

出版信息

J Med Chem. 2021 May 13;64(9):5404-5428. doi: 10.1021/acs.jmedchem.0c01549. Epub 2021 Apr 12.

The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound , a potent DHODH inhibitor (IC = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC = 265 nM). Herein, we investigate the drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, is characterized by higher potency in inducing myeloid differentiation (EC = 17.3 nM), strong proapoptotic properties (EC = 20.2 nM), and low cytotoxicity toward non-AML cells (EC(Jurkat) > 100 μM).

二氢乳清酸脱氢酶（DHODH）是嘧啶生物合成的关键酶，与急性髓细胞性白血病（AML）的关联引起了制药行业的极大兴趣，可能成为 AML 的治疗靶点。我们最近发现化合物是一种有效的 DHODH 抑制剂（IC = 1.2 nM），能够在低纳摩尔范围内（EC = 32.8 nM）诱导 AML 细胞系（THP1）中的髓样分化，优于 brequinar 的 I/II 期临床试验（EC = 265 nM）。在此，我们研究了该化合物的类药性，观察到在 10 和 25 mg/kg 剂量下，每 3 天给药一次，连续 5 周（Balb/c 小鼠）时具有良好的代谢稳定性和无毒特征。此外，为了确定候补化合物，我们研究了该类化合物的 SAR。在该系列中，化合物具有更高的诱导髓样分化能力（EC = 17.3 nM），较强的促凋亡特性（EC = 20.2 nM），对非 AML 细胞的低细胞毒性（EC（Jurkat）> 100 μM）。