Design and Synthesis of a Novel Covalent Dihydropteridinone Derivative as a Highly Potent and Orally Bioavailable PLK1 Inhibitor for the Treatment of Chronic Myeloid Leukemia
Polo-like kinase 1 (PLK1) is a validated cancer therapeutic target, but ATP-competitive PLK1 inhibitors have been limited by dose-limiting toxicities. Here, we designed covalent inhibitors that specifically engage the noncatalytic Cys67 residue of the ATP domain. Rational optimization of the warhead and core scaffold led to B9 as a highly potent lead candidate. B9 exhibited low nanomolar enzymatic inhibition and exceptional cellular potency (IC 50 = 0.4 nM in K562 leukemia cells), representing a >150-fold improvement over the reversible reference compound BI2536 (61 nM). B9 also showed favorable overall selectivity against nonrelated kinases. Remarkably, B9 achieved 77.6% oral bioavailability in mice. In an orthotopic K562 leukemia xenograft model, oral administration of B9 significantly suppressed the bioluminescence of leukemia burden and extended survival rates to 100% over 42 days without observable toxicity. These findings underscore the potential of B9 as a safe, orally bioavailable, and highly potent PLK1 inhibitor for preclinical development.
Authors
- Siyu Xiu (ORCID: https://orcid.org/0000-0002-1676-5900)
- Dehua Lu (ORCID: https://orcid.org/0000-0003-0399-7769)
- Ruqiu Zheng
- Zhenming Liu (ORCID: https://orcid.org/0000-0002-8993-4015)
- Jiaxu Zhou (ORCID: https://orcid.org/0000-0002-7720-0700)
- Zhongtang Li (ORCID: https://orcid.org/0000-0001-7996-9911)
- X P
- Weiping Lyu
- Liangren Zhang (ORCID: https://orcid.org/0000-0002-7362-9497)
- Qi Li (ORCID: https://orcid.org/0000-0001-8476-6115)
- Tengfei Li (ORCID: https://orcid.org/0000-0001-6142-3865)
- Yanming Chen (ORCID: https://orcid.org/0000-0001-6255-0938)
- Xiaojiao Sun (ORCID: https://orcid.org/0000-0001-7741-3274)
- Xiangyu Zhang (ORCID: https://orcid.org/0009-0000-1839-646X)
- T T Yang
- Zhongwei Wang
- Yu Lin
- J Q Du
- Jinghao Yan
- Cheng Shi
Institutions
- Shihezi University (CN)
- Zhejiang Chinese Medical University (CN)
- Xinjiang Medical University (CN)
- Peking University (CN)
- Ministry of Education (SA)
- Center for Children (US)
- Drug Discovery Laboratory (Norway) (NO)
- Beijing Children’s Hospital (CN)
- Institute for Advanced Studies in Aging and Geriatric Medicine (US)
- State Key Laboratory of Natural and Biomimetic Drugs (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-06-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01512
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Ministry of Education of the People's Republic of China
- China Postdoctoral Science Foundation
- Science and Technology Department of Zhejiang Province