Design, Synthesis, and Biological Evaluation of 4‑Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3‑Kinases and Histone Deacetylases

Polypharmacology
is a promising paradigm in modern drug discovery.
Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors
in which the hydroxamic acid moiety as the zinc binding functional
group was introduced to a quinazoline-based PI3K pharmacophore through
an appropriate linker. Systematic structure–activity relationship
studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies
and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression
of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis
in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show
significant in vivo anticancer efficacies with tumor growth inhibitions
of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall,
this work shows promise in discovering new anticancer therapeutics
by the approach of simultaneously targeting PI3K and HDAC pathways
with a single molecule.

多靶点药理学（Polypharmacology）是现代药物研发领域极具前景的研究范式。本研究中，我们发现了一系列新型磷脂酰肌醇3-激酶（PI3K）与组蛋白去乙酰化酶（HDAC）双靶点抑制剂：其中将作为锌结合功能基团的异羟肟酸（hydroxamic acid）片段，通过适宜的连接臂引入至基于喹唑啉（quinazoline）的PI3K药效团（pharmacophore）中。经系统的构效关系研究，我们获得了先导化合物23与36，二者可同时以纳摩尔级活性抑制PI3K与HDAC，并展现出良好的抗增殖活性。化合物23与36可有效调控磷酸化AKT（p-AKT）与乙酰化组蛋白H3（Ac-H3）的表达水平，阻滞HCT116癌细胞的细胞周期并诱导其凋亡。完成药代动力学研究后，我们进一步在HCT116与HGC-27异种移植瘤模型中评估了化合物23的体内抗肿瘤活性：其分别以口服（po，150 mg/kg）与腹腔注射（ip，30 mg/kg）给药方式，实现了45.8%与62.6%的肿瘤生长抑制率。综上，本研究通过单分子同时靶向PI3K与HDAC通路的策略，为新型抗肿瘤治疗药物的研发提供了颇具前景的方向。