c-Kit

Mast/stem cell growth factor receptor (SCFR), also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117, is a receptor protein-tyrosine kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. c-Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane segment, and a protein kinase domain that contains an insert of about 80 amino acid residues. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity.

1048007-93-7
Masitinib mesylate
1048007-93-7
1123837-84-2
Sitravatinib
1123837-84-2
B0084-457687
DCC-2618
1225278-16-9
152459-95-5
Imatinib
152459-95-5
B0084-007732
Avapritinib
1703793-34-3
220127-57-1
Imatinib Mesylate
220127-57-1
B0084-313239
SU11652
326914-10-7
B0084-108953
Telatinib
332012-40-5
B0084-091881
Dovitinib
405169-16-6
B0084-069090
Motesanib
453562-69-1
B0084-077384
Masitinib
790299-79-5
850879-09-3
Amuvatinib
850879-09-3
B0084-153042
Motesanib Diphosphate
857876-30-3
B0084-474894
Flumatinib
895519-90-1
ISCK03
945526-43-2

Background


The receptor tyrosine kinase c-Kit (also known as CD117) is a type of transmembrane receptor protein with tyrosine kinase activity encoded by the retroviral proto-oncogene c-Kit. c-Kit kinase includes an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain is located at the N-terminus and contains 520 amino acids. It is composed of five immunoglobulin-like domains (D1~D5), of which D1~D3 are ligand binding regions, and D4~D5 are monomer dimerization regions. The transmembrane domain contains 23 amino acids. The intracellular domain, (also known as the tyrosine kinase domain), is located at the C-terminus and contains 433 amino acids and is subdivided into the proximal membrane (JMD), adenosine triphosphate (ATP) binding domain, kinase insertion region, and A-loop region. The c-Kit kinase usually presents two kinds of conformations: activation and non-activation, and there is a dynamic balance between them.

Activation of c-Kit kinase by stem cell growth factors leads to a dimer resulting in transmembrane phosphorylation of Tyr568 and Tyr570 in JMD. Then, it alters the three-dimensional structure of JMD and weakens its interaction with the kinase's active site, ie, attenuates the autoinhibitory effect of the kinase. This results in the phosphorylation of the kinase domain, which in turn recruits downstream signaling molecules that ultimately activate downstream signaling pathways that regulate cell growth and proliferation. c-Kit plays an important role in occurrence, development, invasion, migration and recurrence of many kinds of tumors. c-Kit activating mutation was firstly found in the human mast cell leukemia cell line (HMC-1), that is the V560G mutation in JMD and the D816V mutation in the kinase domain. Both of these mutations can cause tyrosine autophosphorylation, resulting in non-ligand-dependent activation of c-Kit. The commonly used c-Kit activating mutation sites occur mainly in the extracellular domain (exons 8 and 9), intracellular JMD (exon 11), and the A-loop region in the kinase domain (exon 17). These mutations will destroy the self-inhibitory mechanism of c-Kit, leading to its sustained activation and promote the development of tumors. It is worth mentioning that there are differences in common c-Kit mutations in different tumors. In gastrointestinal stromal tumors (GIST), c-Kit activation mutations occur in approximately 80% of the cases, and these mutations mainly occur in exon 11 (eg, V560D), followed by exon 9. In the case of melanoma, common c-Kit activating mutations occur in exons 11 and 13, such as L576P and K642E. As for systemic mastocytosis (SM) and nuclear-associated factor-associated acute myeloid leukemia (AML) cells, c-Kit activating mutations mainly occur in exon 17, such as D816V/H/Y.

The activating mutation of c-Kit is closely related to the occurrence and development of many kinds of tumors. Therefore, it has become an effective target for tumor treatment, and its inhibitor has become a hot spot for the research and development of antitumor drugs. Imatinib (GleevecTM), which has achieved great success in clinical treatment, is the first marketed c-Kit kinase inhibitor. It is an internationally accepted medication for the treatment of Chronic myeloid leukemia (CML) and GIST. Since 2001, there are currently nine c-Kit kinase inhibitor drugs, including GleevecTM (targets: c-Kit, PDGFR α and Bcr-Abl), NexavarTM (targets: c-Kit, PDGFR, FLT3, VEGFR, FGFR, and Raf), SutentTM (targets: c-Kit, VEGFR, PDGFR, FLT3, GSF1R, Ret), VotrientTM (targets: c-Kit, PDGFR, VEGFR), and CometriqTM (targets: c-Kit, VEGFR2, c-Ret, c-Met, FLT3), etc. There are several different structural types of c-Kit kinase inhibitors in the phase of clinical trials, such as lenvatinib (targets for differentiated thyroid cancer, liver cancer), midostaurin (targets for AML), etc. It is worth mentioning that since most c-Kit kinase inhibitors are ATP-competitive inhibitors, and there is a high homology between different types of tyrosine kinases, currently on the market c-Kit inhibitors are multi-target inhibitors. They inhibit not only c-Kit but also other types of tyrosine kinases.

The success of c-Kit kinase inhibitors in the molecular targeted therapy of tumors is indeed very encouraging, but unfortunately, some tumor patients will suffer drug resistance after using them for a period of time. The mechanism of drug resistance is very complex, including kinases secondary point mutations in the domain, amplification and overexpression of target genes or activation of epigenetic regulation, upregulation or activation of redundant/downstream signaling pathways, and overexpression of ABC transporters. Among them, the drug resistance caused by the secondary point mutation of the kinase domain is particularly prominent, which seriously affects the efficacy of the existing protein kinase inhibitors. The c-Kit resistance mutations mainly occur in the ATP binding region (exons 13 and 14) and the kinase domain A-loop region (exon 17). With the in-depth clarification of the mechanism of resistance mutation of c-Kit kinase, it will help to solve the problem of tumor resistance.

BOC Sciences can provide many c-Kit kinase inhibitors with high quality. BOC Sciences is equipped with advanced equipment and professional responsible staffs are available for your service. For more detail information and more customized solution, please do not hesitate to contact us. We are ready for your service all the time.

References:

1.Furitsu, T., Tsujimura, T., Tono, T., Ikeda, H., Kitayama, H., Koshimizu, U., Sugahara, H., Butterfield, J. H., Ashman, L. K., Kanayama, Y., (1993) Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 92(4):1736-1744

2. Edris, B., Willingham, S. B., Weiskopf, K., Volkmer, A.K., Volkmer, J.P., Mühlenberg, T., Montgomery, K.D., Contreras-Trujillo, H., Czechowicz, A., Fletcher, J.A., West, R.B., Weissman, I.L., van de Rijn, M., (2013) Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth. Proc Natl Acad Sci USA, 2013, 110(9): 3501-3506.

3. Beadling, C., Jacobson-Dunlop, E., Hodi, F.S., Le, C., Warrick, A., Patterson, J., Town, A., Harlow, A., Cruz, F., Azar, S., Rubin, B.P., Muller, S., West, R., Heinrich, M.C., Corless, C.L., (2008) Kit gene mutations and copy number in melanoma subtypes. Clin Cancer Res, 14(21): 6821-6828.

4. Erben, P., Schwaab, J., Metzgeroth, G., Horny, H.P., Jawhar, M., Sotlar, K., Fabarius, A., Teichmann, M., Schneider, S., Ernst, T., Müller, M.C., Giehl, M., Marx, A., Hartmann, K., Hochhaus, A., Hofmann, W.K., Cross, N.C., Reiter, A., (2014) The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol, 93(1): 81-88.