ATP-competitive TKIs have off-target effects that can cause intolerance1
Selectivity of kinase inhibitors: Kinases bound by ATP-competitive TKIs are indicated by red circles2
- Protein kinases are involved in many diseases (such as cancer and inflammation) and are important targets for drug development3
- Most kinase inhibitors target the kinase ATP site, allowing the potential for cross-reactivity4
- ATP-competitive TKIs approved for CML therapy bind to kinases in addition to their intended target5
- Off-target binding can modulate unintended biological pathways and may contribute to the short- and long-term safety profiles of TKIs6
AGC, protein kinase families A, G, and C; ATP, adenosine triphosphate; CAMK, calmodulin-dependent protein kinase; CK1, casein kinase 1; CMGC, cyclin-dependent kinase, mitogen-activated protein kinase, glycogen synthase kinase, and CDC-like kinase; CML, chronic myeloid leukemia; STE, sulfotransferase; TKI, tyrosine kinase inhibitor; TKL, tyrosine kinase-like; ABL1, Abelson tyrosine kinase 1; BCR, breakpoint cluster region; TKI, tyrosine kinase inhibitor
References
De Santis S, Monaldi C, Mancini M, Bruno S, Cavo M, Soverini S. Overcoming resistance to kinase inhibitors: the paradigm of chronic myeloid leukemia. OncoTargets and therapy. 2022 Jan 25:103-16.
Lee H, Basso IN, Kim DD. Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia. International journal of hematology. 2021 May;113(5):632-41.
Theivendren P, Kunjiapрап S, Hegde YM, Vellaichamy S, Gopal M, Dhramalingam SR. Importance of Protein Kinase and. Protein Kinases: Promising Targets for Anticancer Drug Research. 2021 Dec 8:75.
Miranda RR, Zhang C. Reactivity-based chemical-genetic study of protein kinases. RSC Medicinal Chemistry. 2022;13(7):783-97.
Thomson RJ, Moshirfar M, Ronquillo Y. Tyrosine kinase inhibitors. InStatPearls [Internet] 2023 Jul 18. StatPearls Publishing.
Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduction and Targeted Therapy. 2023 Jul 7;8(1):262.
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