2. Academic Validation
  3. Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity

Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity

  • J Med Chem. 2021 Oct 28;64(20):15379-15401. doi: 10.1021/acs.jmedchem.1c01451.
Linyu Yang 1,  Wanhua Zhang 1 2,  Qiang Qiu 1,  Zhengying Su 1,  Minghai Tang 1,  Peng Bai 1,  Wenting Si 1,  Zejiang Zhu 1,  Yan Liu 1,  Jianhong Yang 1,  Shuang Kuang 1,  Jiang Liu 1,  Wei Yan 1,  Mingsong Shi 1,  Haoyu Ye 1,  Zhuang Yang 1,  Lijuan Chen 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
  • 2 Department of Hematology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
PMID: 34648295 DOI: 10.1021/acs.jmedchem.1c01451
Abstract

Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 Inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, 12b showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast Cancer and osimertinib-resistant non-small-cell lung Cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of 12b could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that 12b, as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.

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