Discovery of Potent and Orally Bioavailable Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for the Treatment of Osteosarcoma
Discovery of Potent and Orally Bioavailable Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for the Treatment of Osteosarcoma
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DOI：
10.1021/acs.jmedchem.1c01732
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发表时间：
2022-04-14
影响因子：
7.3
通讯作者：
Liu, Zhiguo
中科院分区：
文献类型：
--
作者：
Chen, Xiaojing;Liu, Lu;Liu, Zhiguo
血小板衍生生长因子受体（PDGFRs）目前被认为是治疗骨肉瘤的有希望的靶点。本文研究了新型嘧啶-2,4-二胺衍生物选择性抑制PDGFR α / β激酶的设计、合成和构效关系（SAR）。筛选级联结果显示，在这些衍生物中，7nm是首选化合物，PDGFR α和PDGFR β的ic50值分别为2.4和0.9 nM。此外，3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑（MTT）实验表明，7ma对骨肉瘤癌细胞具有明显的细胞毒作用；在异种移植物模型中也显示出强大的抗肿瘤作用和低毒性。此外，7m7具有良好的生物利用度（F= 62.9%）、适宜的半衰期（T1/2= 2.12 h）、令人满意的代谢稳定性和较弱的CYP异构体抑制活性，提示7m7是治疗pdgfr驱动型骨肉瘤的潜在候选药物。
Platelet-derived growth factor receptors (PDGFRs) are now considered promising targets for the treatment ofosteosarcoma. Herein, the design, synthesis, and structure-activity relationships (SAR) of novel pyrimidine-2,4-diamine derivativesthat selectively inhibit PDGFR alpha/beta kinases have been studied. The screening cascades revealed that7mwas the preferred compoundamong these derivatives, with IC50values of 2.4 and 0.9 nM for PDGFR alpha and PDGFR beta, respectively. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) experiment revealed that7mhas a substantial cytotoxic effect againstall osteosarcoma cancer cell lines;7malso displayed robust antitumor effects and low toxicity in a xenograft model. Additionally,7mshowed excellent bioavailability (F= 62.9%), suitable half-life (T1/2= 2.12 h), satisfactory metabolic stability, and weak CYP isoforminhibitory activity, suggesting that7mis a potential drug candidate for PDGFR-driven osteosarcoma.