Pathway Imatinib Pathway, Pharmacokinetics/Pharmacodynamics

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Imatinib Mesylate (Gleevec, Glivec) is a small molecule inhibitor of protein tyrosine kinases. It is used to treat different types of leukemia, in particular, Philadelphia chromosome positive chronic myeloid leukemia (CML), as well as gastrointestinal stromal tumors(GIST) that harbor KIT mutations, and various other types of cancer [PharmGKB: PA162373086].

In more than 90% of patients with CML, the Philadelphia chromosome translocation (t(9;22)) results in the molecular juxtaposition of two genes, BCR and ABL1, to form an the BCR-ABL gene [Articles:12755554, 13679030, 11287972]. The chimeric BCR-ABL oncoprotein formed from the aberrant gene is a constitutively active tyrosine kinase[Articles:12755554, 13679030, 11287972, 11870247] involved in several signal transduction pathways [Article:11870247]. A host of substrates can be phosphorylated by BCR-ABL [Articles:19064740, 11071626] and references therein. The BCR-ABL tyrosine kinase is the critical pathogenetic event in CML [Article:19064740]. Imatinib binds to the BCR-ABL protein and inhibits its activity [Articles:12755554, 13679030, 16122278, 11287972]. This results in inhibition of proliferation and induction of apoptosis in BCR-ABL -positive cells, with no effect on normal cells [Article:16122278]. In the case of GIST, mutations in KIT produce ligand-independent constitutive activation of KIT [Articles:9438854, 18369405]. Imatinib interrupts KIT-mediated signal transduction in a manner analogous to its inhibition of BCR-ABL [Articles:11870247, 16122278, 17385949].

Besides BCR-ABL protein kinase and c-KIT, imatinib is also known to inhibit other protein kinases such as PDGF-R [Articles:15828850, 16122278, 11870247, 17385949]. Proteins encoded by DDR1, DDR2, CSF1R, LCK, BLK, PDGFRA, PDFRB were also found, in in vitro binding assays, to bind imatinib with Kd's less than 1uM.[Article:18183025]

Imatinib is primarily metabolized by CYP3A4 and CYP3A5 to an active metabolite, an N-demethylated piperizine derivative (CGP 74588), as well as various other metabolites [Articles:16122278, 15828850, 16006570]. CGP 74588 has a similar potency to that of the parent drug; the elimination half-lives are approximately 13 hours for the parent and 20 hours, for the metabolite, respectively [Articles:16122278, 16006570]. Other enzymes that play a minor role in metabolism are CYP1A2, CYP2D6, CYP2C9 and CYP2C19 [Article:16122278]. Imatinib is excreted mainly as its metabolites [Article:16122278].

Imatinib may interact with drugs that are inhibitors or inducers of, or substrate for, CYP3A4. [Articles:17385949, 16122278]. It is also a competitive inhibitor of CYP2C9, CYP2D6, and CYP3A5 [Articles:17385949, 16122278].

The drug is a transported by P-glycoprotein (ABCB1) [Articles:18449471, 16122278, 15828850]and Breast Cancer Resistance Protein (ABCG2) [Articles:18449471, 16122278, 19111841]. With respect to ABCB1, among the patients homozygous for allele 1236C>T (rs1128503), 85% achieve a BCR-ABL level 3 log reduction when treated with imatinib, versus 47.7% for the other genotypes. [Article:18524988] The mechanism of resistance to imatinib appears to be due a variety of factors, including BCR-ABL gene amplification [Articles:11423618, 10688835], mutations in the protein that could alter binding [Articles:14534339, 11567109], or over-expression of transporters [Article:14724652].

Many researchers have detected, in a proportion of patients who have developed resistance to imatinib, point mutations in the ABL kinase domain that lead to specific single amino acid substitutions, which could interfere with binding of the drug to the kinase (for a list see [Article:14534339]). However, in in vitro binding studies, while many of these proteins with a single mutation show an increased IC50 vs wild type protein, many other of these mutant proteins are still inhibited by imatinib [Article:12576318].

There are several crystal structures of imatinib, complexed to different proteins, in the Protein Data Bank [Article:10592235]. A crystal structures of imatinib complexed with the human ABL1 kinase domain (2hyy, resolution 2.4A [Article:17164530] ) is available in the PDB. A crystal structure of imatinib complexed with KIT tyrosine kinase (1t46, 1.6A resolution [Article:15123710] ) is also present in the repository. In addition, there is a crystal structure of the drug complexed with SYK tyrosine kinase (1xbb, resolution 1.57A, [Article:15507431]).

Authors: Connie Oshiro.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (11)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
BCR-ABL (ABL1, BCR) BCR-ABL (ABL1, BCR) imatinib 11287972, 12755554, 13679030, 16122278
imatinib CGP 74588 CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5 15828850, 16122278
imatinib Inactive metabolites CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5 15828850, 16122278
KIT KIT imatinib 11870247, 16122278, 17385949
imatinib imatinib ABCB1, ABCG2 15828850, 16122278, 18449471, 19111841
imatinib imatinib ABCB1, ABCG2 15828850, 16122278, 18449471, 19111841
imatinib imatinib
imatinib imatinib
imatinib imatinib

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