Discovery of novel thiophene[3,2-d]pyrimidine-based tubulin inhibitors with enhanced antitumor efficacy for combined use with anti-pd-l1 immunotherapy in melanoma

Article

Author: Wang, Yuxi ; Chen, Jianjun ; Peng, Xiaopeng ; Zhao, Huiting ; Li, Ling ; Liu, Jin ; Wu, Chengyong ; Xu, Chenglong

Herein, we designed and synthesized a series of novel 2-methylthieno [3,2-d]pyrimidine analogues as tubulin inhibitors with antiproliferative activities at low nanomolar levels. Among them, compound DPP-21 displayed the most potent anti-proliferative activity against six cancer cell lines with an average IC₅₀ of ∼6.23 nM, better than that of colchicine (IC₅₀ = 9.26 nM). DPP-21 exerted its anti-cancer activity by suppressing the polymerization of tubulin with an IC₅₀ of 2.4 μM. Furthermore, the crystal structure of DPP-21 in complex with tubulin was solved by X-ray crystallography to 2.94 Å resolution, confirming the direct binding of DPP-21 to the colchicine site. Moreover, DPP-21 arrested the cell cycle in the G2/M phase of mitosis, subsequently inducing tumor cell apoptosis. Additionally, DPP-21 was able to effectively inhibit the migration of cancer cells. Besides, DPP-21 exhibited significant in vivo anti-tumor efficacy in a B16-F10 melanoma tumor model with a TGI of 63.3 % (7 mg/kg) by intraperitoneal (i.p.) injection. Notably, the combination of DPP-21 with NP-19 (a PD-L1-targeting small molecule inhibitor reported by our group before) demonstrated enhanced anti-cancer efficacy in vivo. These results suggest that DPP-21 is a promising lead compound deserving further investigation as a potential anti-cancer agent.

01 Aug 2024·Bioorganic & Medicinal Chemistry Letters

Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors

Article

Author: Cheng, Li ; Ma, Yufeng ; Wang, Ting ; Chen, Jingkao ; Zhao, Peiliang ; Zhang, Mengting ; Ma, Xuanxuan ; Li, Rou

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC₅₀ value of 6.90 μM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G₂/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.

01 Jul 2024·European Journal of Medicinal Chemistry

Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism

Article

Author: Hu, Laixing ; Wang, Tianqi ; Liu, Yonghua ; Tian, Jiaqi ; Gong, Jianhua ; Wang, Chengxi ; Zhang, Junyi

A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC₅₀ values of 0.81-31.19 nM) against five different cancer cells including multidrug-resistant MCF7/ADR cells. Compound 15 displayed a high cancer cell selectivity (IC₅₀(L02)/average IC₅₀: SI = 7.7). The l-valine prodrug 7a and the phosphate prodrug 15a exerted rohust in vivo antitumor efficacies and accepted safety prolifes. Further mechanism studies revealed that 7 and 15 directly bind to the colchicine site in tubulin to block tubulin polymerization, promote microtubule fragmentation at the cellular level, and induce apoptosis with G2/M cell cycle arrest. These compounds also inhibit HEMC-1 cells migration and vascular tube formation. Additionally, compound 7 displayed a selective inhibition of Topo I. Collectively, these studies suggest that 7 and 15 represents a promising new generation of tubulin inhibitors for cancer treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Colonic Cancer	Preclinical	DE	ALTANA Pharma AG	21 Sep 2006

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