Tubulin inhibitors(University of Stellenbosch)

Acute myelocytic leukemia (AML) is a common leukemia subtype in adults, necessitating novel, potent treatments. Microtubule-targeting agents (MTAs) are key anti-cancer drugs widely used in clinical practice. A series of novel furan-trimethoxyphenyl hybrids as tubulin polymerization inhibitors were designed using a molecular combination strategy and evaluated for their structure-activity relationships (SARs) in AML. SAR studies demonstrated that the trimethoxyphenyl unit and substituents on benzyl units play significant roles for the antiproliferative activity against human AML cells. Compound III-3 exerted the highest antiproliferative effects on human AML MV-4-11 (IC₅₀ = 74.25 nM), HL-60 (IC₅₀ = 87.99 nM), and THP-1 cells (IC₅₀ = 92.20 nM). Compound III-3 could directly bind to β-tubulin at the colchicine-binding site, thereby disrupting the microtubule network structure. Compound III-3 activated the spindle assembly checkpoint (SAC), promoting M-phase arrest and mitotic catastrophe and activating the mitochondrial apoptotic pathway in AML cells. In the xenograft mouse model constructed with MV-4-11 cells, the tumor-inhibitory rate of compound III-3 (20 mg/kg body weight, 71.40%) was higher than that of the positive control Ara-C (50 mg/kg body weight, 58.41%). Thus, furan-trimethoxyphenyl hybrids are a promising class of tubulin inhibitors with potential therapeutic applications in AML.

Microtubules represent a clinically validated target for anticancer therapy. However, the clinical utility of existing tubulin inhibitors is frequently compromised by the emergence of drug resistance and systemic toxicities. Herein, we designed and synthesized a series of indazole-based Combretastatin A-4 (CA-4) analogues as potent tubulin polymerization inhibitors. Among them, SMU-G4 potently inhibited the proliferation of B16-F10 melanoma cells (IC₅₀ = 4 nM). Moreover, SMU-G4 significantly induced G2/M phase cell cycle arrest and triggered apoptosis, while effectively suppressing tumor cell migration in vitro. Most importantly, SMU-G4 demonstrated potent in vivo antitumor efficacy in a B16-F10 xenograft mouse model (TGI = 74.4%, 15 mg/kg) without inducing significant systemic toxicity or observable adverse effects. These findings suggest that SMU-G4, characterized by its novel scaffold and potent inhibitory profile, serves as a promising lead compound for the development of next-generation microtubule-targeting agents.