CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
Adv Exp Med Biol. 2020;1243:163-179. doi: 10.1007/978-3-030-40204-4_11.
This personal perspective focuses on small-molecule inhibitors of proteostasis networks in cancer-specifically the discovery and development of chemical probes and drugs acting on the molecular chaperones HSP90 and HSP70, and on the HSF1 stress pathway. Emphasis is on progress made and lessons learned and a future outlook is provided. Highly potent, selective HSP90 inhibitors have proved invaluable in exploring the role of this molecular chaperone family in biology and disease pathology. Clinical activity was observed, especially in non small cell lung cancer and HER2 positive breast cancer. Optimal use of HSP90 inhibitors in oncology will likely require development of creative combination strategies. HSP70 family members have proved technically harder to drug. However, recent progress has been made towards useful chemical tool compounds and these may signpost future clinical drug candidates. The HSF1 stress pathway is strongly validated as a target for cancer therapy. HSF1 itself is a ligandless transcription factor that is extremely challenging to drug directly. HSF1 pathway inhibitors have been identified mostly by phenotypic screening, including a series of bisamides from which a clinical candidate has been identified for treatment of ovarian cancer, multiple myeloma and potentially other cancers.
这篇个人观点聚焦于蛋白质稳态网络的小分子抑制剂在癌症中的应用——特别是发现和开发作用于分子伴侣 HSP90 和 HSP70 以及 HSF1 应激途径的化学探针和药物。重点介绍了已取得的进展和经验教训，并提供了未来展望。高活性、高选择性的 HSP90 抑制剂已被证明在探索该分子伴侣家族在生物学和疾病病理学中的作用方面非常有价值。在非小细胞肺癌和 HER2 阳性乳腺癌中观察到了临床活性。HSP90 抑制剂在肿瘤学中的最佳应用可能需要开发创造性的联合策略。HSP70 家族成员已被证明在技术上更难药物化。然而，最近在有用的化学工具化合物方面取得了进展，这些可能为未来的临床候选药物指明方向。HSF1 应激途径作为癌症治疗的靶点已得到充分验证。HSF1 本身是一种无配体的转录因子，直接药物化极具挑战性。HSF1 途径抑制剂主要通过表型筛选来识别，包括一系列双酰胺，其中一种已被确定为治疗卵巢癌、多发性骨髓瘤和可能其他癌症的临床候选药物。
