Leukemia is a type of cancer that affects the blood and bone marrow and characterized by the uncontrolled production and accumulation of blood cells. According to the World Health Organization (WHO), leukemia is among the fifteen most commonly diagnosed cancers worldwide and the eleventh leading cause of mortality. Tyrosine kinase inhibitors are the first-line choice for the treatment of acute or chronic leukemia. However, mutations in tyrosine kinase proteins are the major cause of resistance. Therefore, the discovery of new targeted antileukemic molecules is essential for the treatment of leukemia. Amongst the various tyrosine kinase inhibitors, tubulin inhibitors displayed promising results in preventing the proliferation of cancer cells. Microtubule targeting agents (MTAs) bind with tubulin protein and affect their functionalities in leukemia cells. In this context, recently reported antileukemic tubulin inhibitors viz., synthetic, natural, dual/multi-inhibitors, antibody-drug conjugates etc. have been summarized (2018 to present) in this manuscript. Structure activity relationship (SAR) analysis depicted that the presence of trimethoxy phenyl, chalcone, quinoline, and oxadiazole scaffolds improved the tubulin inhibitory activity against acute lymphoblastic leukemia. The present review also reported the recent patents and clinical trial data related to antileukemic tubulin inhibitors.

2024-11-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

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

作者: Peng, Xiaopeng ; Zhao, Huiting ; Liu, Jin ; Wang, Yuxi ; Li, Ling ; Wu, Chengyong ; Chen, Jianjun ; 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.

2024-06-27·JOURNAL OF MEDICINAL CHEMISTRY

Improved Rigidin-Inspired Antiproliferative Agents with Modifications on the 7-Deazahypoxanthine C7/C8 Ring Systems

Article

作者: van der Westhuyzen, Aletta E. ; Loots, Leigh ; van Otterlo, Willem A. L. ; Conradie, Daleen ; Kornienko, Alexander ; Betancourt, Tania ; Shuster, Charles B. ; Pelly, Stephen C. ; Landfair, Taylor ; Frolova, Liliya V. ; Ashraf, Naghmana ; Kaschula, Catherine H.

To improve their aqueous solubility characteristics, water-solubilizing groups were added to some antiproliferative, rigidin-inspired 7-deazahypoxanthine frameworks after molecular modeling seemed to indicate that structural modifications on the C7 and/or C8 phenyl groups would be beneficial. To this end, two sets of 7-deazahypoxanthines were synthesized by way of a multicomponent reaction approach. It was subsequently determined that their antiproliferative activity against HeLa cells was retained for those derivatives with a glycol ether at the 4'-position of the C8 aryl ring system, while also significantly improving their solubility behavior. The best of these compounds were the equipotent 6-[4-(2-ethoxyethoxy)benzoyl]-2-(pent-4-yn-1-yl)-5-phenyl-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 33 and 6-[4-(2-ethoxyethoxy)benzoyl]-5-(3-fluorophenyl)-2-(pent-4-yn-1-yl)-1,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 59. Similarly to the parent 1, the new derivatives were also potent inhibitors of tubulin assembly. In treated HeLa cells, live cell confocal microscopy demonstrated their impact on microtubulin dynamics and spindle morphology, which is the upstream trigger of mitotic delay and cell death.

100 项与 Tubulin inhibitors(University of Stellenbosch) 相关的药物交易

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