Development of MKI-3: A Potent and Selective MASTL Inhibitor with Improved Efficacy for Cancer Treatment

  • J Med Chem. 2026 Apr 9;69(7):8181-8214. doi: 10.1021/acs.jmedchem.5c03599.
Ji-In Kim  1  2 ,  Ye-Hyun Kim  3  4 ,  Navin Pandit  1 ,  Kyu Myung Lee  1  5 ,  Chong Hak Chae  1 ,  Doyoun Kim  1  6  7 ,  Jae-Sung Kim  3  4 ,  Kwan-Young Jung  1  6
Affiliations
  • 1. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 2. College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea.
  • 3. Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
  • 4. Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 5. Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 6. Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 7. School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
PMID: 41857504 DOI: 10.1021/acs.jmedchem.5c03599
Abstract

Microtubule-associated serine/threonine kinase-like (MASTL) is a primary regulator of Mitosis and a potential Cancer target. We report the discovery and optimization of MASTL kinase inhibitor-3 (MKI-3), a potent and selective MASTL Inhibitor with nanomolar cellular activity and enhanced metabolic stability, suitable for in vivo assessment. Structure-activity relationship studies identified MKI-3, a quinazoline-based scaffold that enhances MASTL binding, suppresses endosulfine alpha (ENSA) phosphorylation, and activates protein Phosphatase 2A. MKI-3 inhibited MASTL with a half-maximal inhibitory concentration of 5.72 nM and exhibited strong selectivity over Other AGC kinases. In breast Cancer cell lines (MCF7, MDA-MB-231, BT549, and 4T1), MKI-3 exhibited robust antiproliferative effects at nanomolar concentrations. Mechanistically, MKI-3 disrupted the MASTL-ENSA-Aurora A signaling axis, inducing chromosomal instability, mitotic catastrophe, and Apoptosis. MKI-3 significantly reduced tumor growth in treatment-refractory 4T1 triple-negative breast Cancer without toxicity and outperformed MKI-2 supporting MASTL-targeted therapy.

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