Discovery, Synthesis, and Biological Evaluation of 1,3,4,5-Tetrahydro-6H-pyrano[4,3-c]isoquinolin-6-one Derivatives as Novel and Highly Selective PARP1 Inhibitors.
Aug 2026· Journal of Medicinal Chemistry· Vol 69 15, pp.
18051-18075
· 0 citations· 32 references
Medicine
TL;DR
(R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold, is developed and established as a promising candidate and the design strategy for the next-generation PARP1-targeted therapy is validated.
Abstract
Developing highly selective PARP1 inhibitors is a promising strategy to improve the therapeutic window compared with dual PARP1/2 inhibitors. Through structure-guided design and optimization, we developed (R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold. It demonstrates nanomolar enzymatic potency (PARP1 IC50 = 2.4 nM), exceptional 65.8-fold selectivity over PARP2, and robust antiproliferative activity in BRCA-deficient cells. (R)-A17 exhibits favorable pharmacokinetic properties with complete oral bioavailability (F = 100%) in mice. Mechanistically, it selectively inhibits PARP1-mediated PARylation and induces DNA damage and G2/M phase arrest. In vivo, oral administration of (R)-A17 produced dose-dependent antitumor efficacy in BRCA mutant xenograft models, achieving tumor growth inhibition values of 57.8, 86.3, and 91.3% at doses of 0.3, 1, and 3 mg/kg, respectively, while also synergizing effectively with liposomal irinotecan in an HCT116 xenograft model. These results establish (R)-A17 as a promising candidate and validate the design strategy for the next-generation PARP1-targeted therapy.
Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising therapeutic target due to its critical roles in regulating fundamental cellular processes such as proliferation, migration, and differentiation. Although several PRMT5 inhibitors have been reported, but none have gained clinical approval. Herein, we describe the discovery of a novel series of benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones derivatives as MTA cooperative PRMT5 inhibitors. Compound 9u exhibited significant antiproliferative activity in MTAP-deleted HCT116 cancer cells, with an IC50 value of 13 nM, exhibiting 70-fold selectivity over MTAP wild type HCT116 cells. Furthermore, 9u displayed robust efficacy across diverse MTAP-deleted cancer cell lines, achieving IC50 values of <1.5-51 nM. Notably, it also showed favorable metabolic stability in both human and mouse liver microsomes. These findings establish a promising lead for the development of PRMT5-MTA inhibitors specifically targeting MTAP-deficient cancers.
Bing Liu, Shao-Yan Li, Hui Shi et al.· Bioorganic chemistry (Print)· 0 citations
Rho-associated coiled-coil-containing kinase 2 (ROCK2) is a key regulator of cellular motility and invasion and represents a promising therapeutic target for metastatic breast cancer. Through systematic structure-activity relationship (SAR) studies, we designed and synthesized a novel series of 1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione derivatives as selective ROCK2 inhibitors. Strategic deuterium incorporation during structural optimization was employed to enhance pharmacokinetic profiles. This effort led to the identification of compound 22d, a highly potent deuterated analog with excellent ROCK2 inhibitory activity (IC50 = 13 nM) and remarkable selectivity (≥769-fold over ROCK1). In functional assays, 22d exhibited robust antimetastatic activity in vitro and significantly suppressed tumor metastasis in MDA-MB-231 breast cancer xenograft models. Mechanistically, its antimetastatic effects were attributed to selective inhibition of STAT3 phosphorylation at tyrosine 705 (Y705). Collectively, these findings establish 22d as a novel lead compound that impairs breast cancer metastasis through targeted disruption of the ROCK2-STAT3 signaling axis, providing a promising foundation for further therapeutic development against metastatic breast cancer.
Yueshan Li, Liting Zhang, Haixing Xu et al.· Journal of Medicinal Chemist...· 0 citations
Abstract Microtubules assembled from α/β-tubulin heterodimers are critical for cell division and well-established anticancer drug targets, making tubulin polymerization inhibitors a viable route for new chemotherapeutics. Guided by structural analysis of colchicine-site binders and tubulin-ligand computational simulations, we rationally designed and synthesized a series of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidines as novel colchicine-binding site tubulin inhibitors. Derivative 9t displayed the strongest antiproliferative potency, with IC₅。 values of 0.065-0.096 μM across tested cancer lines. It exerted minimal toxicity to normal L929 fibroblasts, yielding a selectivity index over 300. Mechanistic assays confirmed 9t suppresses cell-free tubulin polymerization, destroys cellular microtubule architecture, induces persistent G₂/M cell cycle arrest, and activates cancer cell apoptosis. Overall, 9t serves as a promising dual-function tubulin inhibitor with both cytostatic and cytotoxic anticancer effects, meriting further preclinical investigation.
Jiake Gao, Yujing Zhang, Rui Qu et al.· Journal of Enzyme Inhibition...· 0 citations
A novel series of N-butyl isatin (indolin-2-one) derivatives was designed and synthesized as potential VEGFR-2-targeted anticancer agents, drawing inspiration from the oxindole-based inhibitor sunitinib. The synthesized compounds were assessed for antiproliferative activity against colorectal cancer cell lines (HT29 and HCT116) and for their inhibitory potential on VEGFR-2. Compound 6b exhibited the highest potency, demonstrating strong VEGFR-2 inhibition comparable to that of sunitinib. Mechanistic investigations in HCT116 cells demonstrated that 6b induced G0/G1 cell cycle arrest and promoted apoptosis, which was associated with the upregulation of p53 and Bax, downregulation of Bcl-2, and suppression of Cyclin D1 and Cyclin E expression. Furthermore, 6b markedly decreased VEGF-A expression, supporting modulation of VEGF/VEGFR-2-associated signaling. Molecular docking studies involving VEGFR-2 (PDB ID: 4AGD) demonstrated favorable binding of compound 6b in the ATP-binding pocket, establishing essential interactions with essential residues. Docking validation was established through the successful redocking of sunitinib, yielding an RMSD of 0.44 Å. Additionally, 500 ns molecular dynamics simulations indicated stable backbone behavior, regulated ligand fluctuations, preserved structural compactness, and sustained hydrogen bonding within the 6b-VEGFR-2 complex. The findings collectively identify compound 6b as a promising lead candidate for further development as a VEGFR-2-targeted anticancer agent.
Mohamed El-Naggar, Hend I Abdelaal, Mohamed E Albakri et al.· RSC Advances· 0 citations
Abstract A novel class of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyrazine derivatives was designed and synthesized as tubulin polymerization disruptors. Among them, compound 10t emerged as the most potent agent, exhibiting IC₅。 values of 0.13-0.18 µM against HeLa, SGC‑7901, and MCF‑7 cancer cell lines. Functional studies revealed that 10t effectively inhibits tubulin assembly in vitro, destabilizes cellular microtubule networks, induces G₂/M cell‑cycle arrest, and triggers apoptosis. Molecular docking indicated that 10t binds to the colchicine site on tubulin, forming a unique hydrogen bond with β‑Asn349 that is not observed with the reference compound CA‑4. Importantly, 10t showed significantly lower cytotoxicity toward normal HUVECs than CA‑4, suggesting an improved safety profile. Collectively, these findings establish the pyrazolo[3,4‑b]pyrazine scaffold as a promising platform for microtubule‑targeting anticancer agents and identify 10t as a compelling lead for further development.
Zhu Guo, Yujing Zhang, Ping Zou et al.· Journal of Enzyme Inhibition...· 0 citations
Sterol 14α-demethylase (CYP51) and squalene epoxidase (SE) are rate-limiting enzymes in ergosterol biosynthesis, and their inhibition markedly retards fungal growth. A series of novel (1,2,4-triazol-1-yl)propan-2-ol derivatives were designed based on reported CYP51/SE inhibitor scaffolds. Bioassays demonstrated that compound 6o exhibited broad-spectrum antifungal activity, with EC50 values of 0.25, 0.38, and 0.49 mg/L against Valsa mali, Rhizoctonia solani, and Curvularia lunata, respectively. At 100 mg/L, compound 6o achieved 84.6% in vivo control efficacy against V. mali, comparable to difenoconazole (88.1%). Further studies revealed that compound 6o blocked ergosterol synthesis, damaged cell membrane integrity, elevated membrane permeability, and triggered intracellular ROS accumulation in V. mali. Enzyme activity tests, molecular docking, and qRT-PCR analyses suggested that compound 6o acts as a dual inhibitor of CYP51 and SE. Moreover, compound 6o exhibited good biosafety toward apple and rice seedlings. Collectively, compound 6o represents a promising lead for novel demethylation inhibitor fungicides for crop protection.
Jian-Wei Xue, Hai-Nan Luo, Shun-Bai Chen et al.· Journal of Agricultural and...· 0 citations
