Structure of cyclin-dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT-313.,Acta Crystallographica Section F

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Structure of cyclin-dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT-313.
Acta Crystallographica Section F ( IF 1.1 ) Pub Date : 2020-08-03 , DOI: 10.1107/s2053230x20009243
Sumalatha Rani Talapati ₁ , Vijayashankar Nataraj ₁ , Manoj Pothuganti ₁ , Suraj Gore ₁ , Murali Ramachandra ₁ , Thomas Antony ₁ , Sunil Shivaji More ₂ , Narasimha Rao Krishnamurthy ₁

Affiliation

CVT‐313 is a potent CDK2 inhibitor that was identified by screening a purine‐analogue library and is currently in preclinical studies. Since this molecule has the potential to be developed as a CDK2 inhibitor for cancer therapy, the potency of CVT‐313 to bind and stabilize CDK2 was evaluated, together with its ability to inhibit aberrant cell proliferation. CVT‐313 increased the melting temperature of CDK2 by 7°C in thermal stabilization studies, thus indicating its protein‐stabilizing effect. CVT‐313 inhibited the growth of human lung carcinoma cell line A549 in a dose‐dependent manner, with an IC₅₀ of 1.2 µM, which is in line with the reported biochemical potency of 0.5 µM. To support the further chemical modification of CVT‐313 and to improve its biochemical and cellular potency, a crystal structure was elucidated in order to understand the molecular interaction of CVT‐313 and CDK2. The crystal structure of CDK2 bound to CVT‐313 was determined to a resolution of 1.74 Å and clearly demonstrated that CVT‐313 binds in the ATP‐binding pocket, interacting with Leu83, Asp86 and Asp145 directly, and the binding was further stabilized by a water‐mediated interaction with Asn132. Based on the crystal structure, further modifications of CVT‐313 are proposed to provide additional interactions with CDK2 in the active site, which may significantly increase the biochemical and cellular potency of CVT‐313.

中文翻译：

细胞周期蛋白依赖性激酶 2 (CDK2) 与特异性强效抑制剂 CVT-313 复合物的结构。

CVT-313 是一种有效的 CDK2 抑制剂，通过筛选嘌呤类似物库而鉴定，目前正在进行临床前研究。由于该分子有潜力被开发为用于癌症治疗的 CDK2 抑制剂，因此评估了 CVT-313 结合和稳定 CDK2 的效力及其抑制异常细胞增殖的能力。在热稳定研究中，CVT-313 将 CDK2 的解链温度提高了 7°C，从而表明了其蛋白质稳定作用。 CVT-313 以剂量依赖性方式抑制人肺癌细胞系 A549 的生长，IC ₅₀为 1.2 µM ，与报道的 0.5 µM生化效力一致。为了支持 CVT-313 的进一步化学修饰并提高其生化和细胞效力，阐明了晶体结构，以了解 CVT-313 和 CDK2 的分子相互作用。 CDK2 与 CVT-313 结合的晶体结构以 1.74 Å 的分辨率测定，清楚地表明 CVT-313 结合在 ATP 结合口袋中，直接与 Leu83、Asp86 和 Asp145 相互作用，并且通过水介导的与 Asn132 的相互作用。基于晶体结构，建议对 CVT-313 进行进一步修饰，以在活性位点提供与 CDK2 的额外相互作用，这可能会显着提高 CVT-313 的生化和细胞效力。

更新日期：2020-08-03

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