title: Inhibitors of ABL and the ABL-T315I mutation.
abstract: Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd) generation inhibitors with the exception of the T315I mutant. Several 3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.
authors.affiliation: TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA. noronha@targegen.com
authors.forename: Glenn
authors.initials: G
authors.lastname: Noronha
authors.forename: Jianguo
authors.initials: J
authors.lastname: Cao
authors.forename: Chun P
authors.initials: CP
authors.lastname: Chow
authors.forename: Elena
authors.initials: E
authors.lastname: Dneprovskaia
authors.forename: Richard M
authors.initials: RM
authors.lastname: Fine
authors.forename: John
authors.initials: J
authors.lastname: Hood
authors.forename: Xinshan
authors.initials: X
authors.lastname: Kang
authors.forename: Boris
authors.initials: B
authors.lastname: Klebansky
authors.forename: Dan
authors.initials: D
authors.lastname: Lohse
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Mak
authors.forename: Andre
authors.initials: A
authors.lastname: McPherson
authors.forename: Moorthy S S
authors.initials: MS
authors.lastname: Palanki
authors.forename: Ved P
authors.initials: VP
authors.lastname: Pathak
authors.forename: Joel
authors.initials: J
authors.lastname: Renick
authors.forename: Richard
authors.initials: R
authors.lastname: Soll
authors.forename: Binqi
authors.initials: B
authors.lastname: Zeng
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D015394:Molecular Structure; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016315:Proto-Oncogene Proteins c-abl