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. (1st November 2022)

• Record Type: Journal Article
• Authors: Li, Zhi; Zhao, Can; He, Ge; Wang, Yujie; Wang, Yang; Ma, Xiaodong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 73(2022)
• Publication Date: 2022-11-01
• Subjects: PI3K/HDAC dual inhibitors -- SAR study -- Selectivity -- Anti-proliferative -- Immunomodulatory -- Solid tumors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Dual-targeted inhibitors were discovered via building HDAC6 potency in a PI3Kδ-selective template. Compound 59 potently inhibited both PI3Kδ and HDAC6 with acceptable subtype specificity. It exhibited attractive anti-proliferative activities against solid tumor cell lines. It dramatically abated immune escape-related STAT3 signaling and attenuated PD-L1 expression in T47D cells. A new site accessible to structural derivatization was identified. 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.