WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China.
WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
Bioorg Med Chem Lett. 2024 Nov 1;112:129941. doi: 10.1016/j.bmcl.2024.129941. Epub 2024 Sep 1.
Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900).
新兴的临床证据表明，选择性 CDK9 抑制可能为某些癌症的治疗提供临床获益。许多 CDK9 选择性抑制剂已进入临床开发阶段，并正在进行研究。由于这些药物在临床上经常出现不可预见的毒性，因此还没有出现明显的优胜者。因此，仍然需要具有差异化特征的新型药物。在此，我们报告了我们设计、合成新型氮茚系列选择性 CDK9 抑制剂的研究成果。SAR 研究导致了临床前候选药物 YK-2168 的出现。与 AZD4573 和 BAY1251152 相比，YK2168 对 CDK9 的选择性更好；在临床前研究中，在 SNU16 CDX 小鼠胃癌模型中也表现出不同的静脉 PK 特征和显著的实体瘤疗效。YK-2168 目前正在中国进行临床开发（CTR20212900）。
