Discovery and Pharmacological Characterization of a Dual-Acting 2-Amino-3-Cyanopyridine Inhibitor Targeting Microtubule Polymerization and GAK

  • J Med Chem. 2026 Jul 9;69(13):15489-15509. doi: 10.1021/acs.jmedchem.6c00337.
Seulki Park  1 ,  Eun Yeong Kim  2  3 ,  Ji-Eun Lee  4  5 ,  Ahra Go  2 ,  Seung-Jin Park  6 ,  Yehyeong Lee  2  3 ,  Tae-Jun Kim  1  4 ,  Young Jin Seo  2  3 ,  Byul Moon  5 ,  Jin Hwa Cho  1 ,  Joo-Youn Lee  2  3 ,  Seon-Kyu Kim  4  6 ,  Jung-Ae Kim  1  4  5 ,  Yong Hee Cho  2  3 ,  Jeong-Hoon Kim  1  4 ,  Jong Yeon Hwang  2  3
Affiliations
  • 1. Orphan Disease Therapeutic Target Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
  • 2. Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 305-606, Republic of Korea.
  • 3. Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 4. Department of Bioscience, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 5. Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
  • 6. Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
PMID: 42298883 DOI: 10.1021/acs.jmedchem.6c00337
Abstract

Microtubules are critical regulators of mitotic progression and Cancer cell proliferation. Herein, we report a novel 2-amino-3-cyanopyridine-based scaffold that functions as a dual inhibitor of tubulin polymerization and cyclin G-associated kinase (GAK). Structure-activity relationship (SAR) optimization identified KMG-732 with nanomolar to submicromolar cytotoxicity across diverse Cancer cell lines. Mechanistic investigations revealed that KMG-732 targets the colchicine-binding site, effectively disrupting microtubule assembly and triggering mitotic arrest followed by Apoptosis. Beyond its antimitotic effects, KMG-732 significantly attenuates Cancer cell migration and invasion. Importantly, KMG-732 displayed favorable pharmacokinetic properties and showed minimal P-glycoprotein-mediated efflux. KMG-732 demonstrated robust antitumor efficacy in both organoids and in vivo xenograft models, maintaining a superior safety profile with reduced systemic toxicity compared to colchicine. Kinome profiling and biochemical assays confirmed selective GAK inhibition, distinguishing KMG-732 from traditional tubulin inhibitors. Collectively, KMG-732 represents a promising dual-targeting antimitotic lead candidate with enhanced efficacy and therapeutic window for Cancer treatment.

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