1. Academic Validation
  2. Identification of PI3K/HDAC Dual-targeted inhibitors with subtype selectivity as potential therapeutic agents against solid Tumors: Building HDAC6 potency in a Quinazolinone-based PI3Kδ-selective template

Identification of PI3K/HDAC Dual-targeted inhibitors with subtype selectivity as potential therapeutic agents against solid Tumors: Building HDAC6 potency in a Quinazolinone-based PI3Kδ-selective template

  • Bioorg Med Chem. 2022 Nov 1:73:117028. doi: 10.1016/j.bmc.2022.117028.
Zhi Li 1 Can Zhao 1 Ge He 1 Yujie Wang 1 Yang Wang 2 Xiaodong Ma 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China.
  • 2 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China. Electronic address: wangyang1991@ahtcm.edu.cn.
  • 3 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei 230012, China. Electronic address: tgmxd1988@ahtcm.edu.cn.
Abstract

Pharmacological inhibition of PI3Kδ for battling solid tumors is relatively unexplored. Given the potential synergism of concurrent PI3Kδ/HDAC6 inhibition, and the drawbacks of pioneering PI3K/HDAC dual inhibitors, we discovered a novel series of dual-targeted inhibitors via building HDAC6 potency in a PI3Kδ-selective template. SAR study culminated in the discovery of compound 59, which exhibited remarkable inhibitory activity against both PI3Kδ (IC50 = 2.3 nM) and HDAC6 (IC50 = 13 nM), along with acceptable subtype specificity. In addition to the attractive anti-proliferative activities, especially against T47D cell line (IC50 = 0.042 μM), 59 treatment dramatically ablated the tumor immune escape-related STAT3 signaling and lowered PD-L1 expression at two-digit nanomolar level, reflecting the immunomodulatory properties. Due to its subtype selectivity, it demonstrated low cytotoxicity against normal cells. This research validated the therapeutic potential of PI3Kδ/HDAC6 dual inhibitors against solid tumors, attributed to their dual roles in anti-proliferation and Anticancer immunomodulation.

Keywords

Anti-proliferative; Immunomodulatory; PI3K/HDAC dual inhibitors; SAR study; Selectivity; Solid tumors.

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