2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2024 Nov 5:277:116791. doi: 10.1016/j.ejmech.2024.116791.
Chenglong Xu 1,  Chengyong Wu 2,  Ling Li 3,  Huiting Zhao 1,  Jin Liu 4,  Xiaopeng Peng 5,  Yuxi Wang 6,  Jianjun Chen 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 The Eighth Affiliated Hospital Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, 518000, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, 570228, China.
  • 5 College of Pharmacy, Gannan Medical University, Ganzhou, 314000, China.
  • 6 Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China. Electronic address: yuxiwang@scu.edu.cn.
  • 7 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China. Electronic address: jchen21@smu.edu.cn.
PMID: 39197251 DOI: 10.1016/j.ejmech.2024.116791
Abstract

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.

Keywords

2-methylthieno[3,2-d]pyrimidine; Anti-cancer; Combination therapy; Tubulin inhibitors.

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