Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug

Abstract

In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

“…For example, imatinib, a 2-phenylaminopyrimidine-derivative tyrosine kinase inhibitor that principally targets Abl and c-kit, also inhibits the tyrosine kinases of PDGFRa and PDGFRb. 65 Imatinib currently is approved in the United States for the treatment of 1) Philadelphia chromosomepositive chronic myelogenous leukemia and acute lymphoblastic leukemia, both of which have a characteristic bcr-abl translocation and increased kinase activity 66,67 ; and 2) gastrointestinal stromal tumors, which commonly have activating c-kit mutations. 68 Indications for the use of imatinib that arise from imatinib's specific effects on PDGFR include dermatofibrosarcoma protuberans, which has a distinguishing translocation involving PDGF-B, 69 and idiopathic hypereosinophilic syndrome, Tumor stromal cells and stromal-influenced angiogenic factors are important for facilitating PDGF/ PDGFRa-mediated effects on cancer growth, as discussed above.…”

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

“…Imatinib is quite selective for BCR-ABL (the Abelson protooncogene), 4 it inhibits other targets such as KIT and PDGFR (platelet-derived growth factor receptor), 5 and also to a lesser degree it acts on EGFR. 6 Imatinib inhibits these tyrosine kinase enzymes of both cancer cells and non-cancer cells. Therefore, germline genetic polymorphisms of drug targets such as KIT and PDGFRA/B might influence side effects of Imatinib, such as ophthalmological toxicities.…”

Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia

“…4a). Addition of imatinib, a selective inhibitor of ABL1 kinase activity 7 , decreased phosphorylation of both NUP214-ABL1 and CRKL (Fig. 4b) and inhibited the proliferation of ALL-SIL (Fig.…”

“…We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib 7,8 . The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression 1 and deletion of CDKN2A 9 , consistent with a multistep pathogenesis of T-ALL.…”