SRC Family Kinase (SFK) Targeted Library

Defining the Src family kinases as the key players in controlling a variety of cellular processes has made this topic one of the most actively studied domains of drug discovery.

As one of the family, SRC kinase belongs to non-receptor tyrosine kinases essential for cell growth, proliferation, differentiation, survival, adhesion, and migration. The Src kinase family is established to comprise nine members, including SRC, FYN, LCK, YES, BLK, FGR, HCK, LYN, and YRK [1]. They are activated by growth factors, cytokines, G-protein-coupled receptors, and integrin-mediated cell adhesion [2]. Upon activation, SRC kinases phosphorylate many substrates, e.g., cytoskeletal proteins, transcription factors, and signaling proteins [3]. SRC kinases are involved in the regulation of the actin cytoskeleton, endocytosis, cell migration, and adhesion [4].

With so many vital functions, it is not surprising that the dysregulation of SRC kinases results in the formation of many types of cancer, such as breast, colon, lung, and pancreatic cancer [5-8], as well as in the progression of neurodegenerative disorders, namely, Parkinson's and Alzheimer’s [9], cardiovascular and autoimmune skin conditions [10-11]. Therefore, further studies of SRC kinases and their downstream targets are estimated to lead to the development of new therapies to treat the above disorders.

The Life Chemicals team has developed its new Docking Library of 7,500 drug-like screening compounds potentially targeting SRC kinase in response to these drug discovery needs.

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Figure 1. Examples of compounds with the best values of docking scores from the SFK Targeted Library

Compound selection

Probable binding sites of the 2BDJ PDB model were predicted, followed by protein-ligand docking against the Life Chemicals HTS Compound Collection. Also used for the selection were the QikProp descriptors of the Maestro Software.

The resulting compounds were filtered by PAINS, toxic, and reactive criteria to choose those with the best drug candidate properties [12]. In-house MedChem filters were applied to refine the final selection providing over 7,500 drug-like screening compounds potentially targeting SRC kinases.

Key features:

• Method: high-throughput virtual screening (docking), molecular fitting
• X-Ray data used: 2BDJ
• Constraints: no
• Filters used: PAINS, toxic, reactive
• Number of compounds selected: 7572

Figure 2. Spatial structure binding site of the complex of Src kinase with lead docking molecule F2541-0237

References

1. Roskoski R Jr. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res. 2015;94:9-25. doi:10.1016/j.phrs.2015.01.003
2. Ma H, Wang J, Zhao X, et al. Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation. Cell Rep. 2020;30(3):793-806.e6. doi:10.1016/j.celrep.2019.12.075
3. Joshi MK, Burton RA, Wu H, et al. Substrate binding to Src: A new perspective on tyrosine kinase substrate recognition from NMR and molecular dynamics. Protein Sci. 2020;29(2):350-359. doi:10.1002/pro.3777
4. Ma YC, Huang XY. Novel regulation and function of Src tyrosine kinase. Cell Mol Life Sci. 2002;59(3):456-462. doi:10.1007/s00018-002-8438-2
5. Luo J, Zou H, Guo Y, et al. SRC kinase-mediated signaling pathways and targeted therapies in breast cancer. Breast Cancer Res. 2022;24(1):99. Published 2022 Dec 29. doi:10.1186/s13058-022-01596-y
6. Chen J, Elfiky A, Han M, Chen C, Saif MW. The role of Src in colon cancer and its therapeutic implications. Clin Colorectal Cancer. 2014;13(1):5-13. doi:10.1016/j.clcc.2013.10.003
7. Huang WC, Kuo KT, Wang CH, Yeh CT, Wang Y. Cisplatin-resistant lung cancer cells promoted M2 polarization of tumor-associated macrophages via the Src/CD155/MIF functional pathway. J Exp Clin Cancer Res. 2019;38(1):180. Published 2019 Apr 29. doi:10.1186/s13046-019-1166-3
8. Parkin A, Man J, Timpson P, Pajic M. Targeting the complexity of Src signaling in the tumor microenvironment of pancreatic cancer: from mechanism to therapy. FEBS J. 2019;286(18):3510-3539. doi:10.1111/febs.15011
9. Portugal CC, Almeida TO, Socodato R, Relvas JB. Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson's and Alzheimer's diseases. FEBS J. 2022;289(24):7760-7775. doi:10.1111/febs.16197
10. Zhai Y, Yang J, Zhang J, Yang J, Li Q, Zheng T. Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases. Int J Med Sci. 2021;18(5):1216-1224. Published 2021 Jan 14. doi:10.7150/ijms.49241
11. Szilveszter KP, Németh T, Mócsai A. Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases. Front Immunol. 2019;10:1862. Published 2019 Aug 9. doi:10.3389/fimmu.2019.01862
12. Dalgarno D, Stehle T, Narula S, et al. Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds. Chem Biol Drug Des. 2006;67(1):46-57. doi:10.1111/j.1747-0285.2005.00316.x