College of Pharmacy, Keimyung University, Daegu, 704-701, South Korea.
Department of Biochemistry, School of Medicine, Keimyung University, Daegu, 704-701, South Korea.
Eur J Med Chem. 2022 Oct 5;240:114582. doi: 10.1016/j.ejmech.2022.114582. Epub 2022 Jul 6.
HDAC6 and Hsp90, existing as a cytosolic complex play an important role in maintaining the protein homeostasis. The interplay of HDAC6 and Hsp90 has attracted wide attention due to their important role and promise as therapeutic targets in malignant cancers. Therefore, the discovery of dual inhibitors targeting HDAC6 and Hsp90 is of high importance. In the present study, we describe the design, synthesis, and biological evaluation of bifunctional inhibitors against HDAC6 and Hsp90 interplay. In particular, compound 6e shows a significant inhibitory activity against both HDAC6 and Hsp90 with IC values of 106 nM and 61 nM, respectively. Compound 6e promotes the acetylation of HDAC6 substrate proteins such as α-tubulin and Hsp90 via HDAC6 inhibition, and also induces the degradation of Hsp90 clients such as Her2, EGFR, Met, Akt, and HDAC6 via Hsp90 inhibition. Compound 6e consequently furnishes potent antiproliferative effect on gefitinib-resistant H1975 non-small cell lung cancer (NSCLC) with a GI value of 1.7 μM. In addition, compound 6e successfully achieved significant tumor growth inhibition in H1975 NSCLC xenograft model without noticeable abnormal behavior, body weight changes, and apparent ocular toxicity. We conclude that compound 6e constitutes an excellent tool as well as a valuable lead for assessment of Hsp90 and HDAC6 dual inhibition with a single molecule.
HDAC6 和 Hsp90 作为胞浆复合物存在，在维持蛋白质稳态方面发挥着重要作用。由于其在恶性肿瘤中作为治疗靶点的重要作用和潜力，HDAC6 和 Hsp90 的相互作用引起了广泛关注。因此，发现针对 HDAC6 和 Hsp90 相互作用的双抑制剂具有重要意义。在本研究中，我们描述了针对 HDAC6 和 Hsp90 相互作用的双功能抑制剂的设计、合成和生物学评价。特别是，化合物 6e 对 HDAC6 和 Hsp90 均表现出显著的抑制活性，IC 值分别为 106 nM 和 61 nM。化合物 6e 通过抑制 HDAC6 促进 HDAC6 底物蛋白如α-微管蛋白和 Hsp90 的乙酰化，并且通过抑制 Hsp90 诱导 Hsp90 客户如 Her2、EGFR、Met、Akt 和 HDAC6 的降解。因此，化合物 6e 对吉非替尼耐药的 H1975 非小细胞肺癌（NSCLC）具有很强的抗增殖作用，GI 值为 1.7 μM。此外，化合物 6e 在 H1975 NSCLC 异种移植模型中成功地实现了显著的肿瘤生长抑制，没有明显的异常行为、体重变化和明显的眼部毒性。我们得出结论，化合物 6e 是一种极好的工具，也是用单个分子评估 Hsp90 和 HDAC6 双重抑制的有价值的先导化合物。
