2. Academic Validation
  3. Rationally designed BCR-ABL kinase inhibitors for improved leukemia treatment via covalent and pro-/dual-drug targeting strategies

Rationally designed BCR-ABL kinase inhibitors for improved leukemia treatment via covalent and pro-/dual-drug targeting strategies

  • J Adv Res. 2024 Sep 8:S2090-1232(24)00392-8. doi: 10.1016/j.jare.2024.09.008.
Jie Sun 1,  Liang Lou 2,  Chengjun Zhu 3,  Peng Chen 4,  Guanghui Tang 5,  Mingxi Gu 6,  Shu Xia 7,  Xiao Dong 8,  Zhi-Min Zhang 9,  Liqian Gao 10,  Shao Q Yao 11,  Qicai Xiao 12
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: sunj86@mail2.sysu.edu.cn.
  • 2 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: louliang@mail2.sysu.edu.cn.
  • 3 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: chengjzhu@stu2022.jnu.edu.cn.
  • 4 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: chenp268@mail2.sysu.edu.cn.
  • 5 Department of Chemistry, National University of Singapore, Singapore 117543, Singapore. Electronic address: chmtg@nus.edu.sg.
  • 6 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: gumx3@mail2.sysu.edu.cn.
  • 7 Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address: XS15093005014@163.com.
  • 8 Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address: dong-xiao@shu.edu.cn.
  • 9 School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: 13632107756@163.com.
  • 10 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China. Electronic address: gaolq@mail.sysu.edu.cn.
  • 11 Department of Chemistry, National University of Singapore, Singapore 117543, Singapore. Electronic address: chmyaosq@nus.edu.sg.
  • 12 School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: qicaixiao@sr.gxmu.edu.cn.
PMID: 39255927 DOI: 10.1016/j.jare.2024.09.008
Abstract

Background: Chronic Myeloid Leukemia (CML) is a blood Cancer that remains challenging to cure due to drug resistance and side effects from current Bcr-Abl inhibitors. There is an urgent need for novel and more effective Bcr-Abl targeting inhibitors and therapeutic strategies to combat this deadly disease.

Method: We disclose an "OH-implant" strategy to improve a noncovalent Bcr-Abl Inhibitor, PPY-A, by adding a hydroxyl group to its scaffold. By taking advantage of this OH "hot spot", we designed a panel of irreversible covalent kinase inhibitors and hypoxia-responsive pro-/dual-drugs, and their biological activities were studied in vitro, in cellulo and in vivo.

Result: The resulting compound B1 showed enhanced solubility and biological activity. B4 achieved sustained Bcr-Abl inhibition by forming a stable covalent bond with ABL kinase. Hypoxia-responsive prodrug P1 and dual-drugs D1/D2/D3 demonstrated significant anti-tumor effects under hypoxic conditions. The in vivo studies using K562-xenografted mice showed that B1 displayed superior antitumor activity than PPY-A, while P1 and D3 offered better safety profiles alongside significant tumor control.

Conclusion: We have successfully developed a chemical biology approach to convert a known noncovalent Bcr-Abl Inhibitor into more potent and safer inhibitors through covalent and pro-/dual-drug targeting strategies. Our "OH-implant" approach and the resulting drug design strategies have general applicability and hold promise for improvement the performance of various other reported drugs/drug candidates, thereby providing advanced medicines for disease treatment.

Keywords

Cancer; Hypoxia-responsive; Kinase inhibitor; Prodrug; Selectivity.

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