Tyrosine kinases, Abl

BCR-ABL tyrosine kinase that is essential for malignant transformation. Cytogenetic responses to IFN-a therapy were seen in 30-40% of the treated patients with complete responses in about 10%. Long term survival can therefore be expected in these patients. In 2000, the BCR-ABL tyrosine kinase inhibitor Imatinib has been introduced for CML therapy and meanwhile has proven more efficient than IFN-a therapy. 

Peng H, Huang N, Qi J, Xie P, Xn C, Wang J, Yang C. Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtnal screening. Bioorg Med Chem Lett 2003 13 3693-9. 

The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxic-ities in older patients. The adverse prognostic factor, the Philadelphia chromosome, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.17 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR-ABL tyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone,... 

BCR-ABL tyrosine kinase Cancer Point mutation causes resistance to STI-571 compound 21... 

Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capde-ville R, Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N. Engl J Med 2001 344 1084-1086. 

Abstract The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Imatinib, a 2-phenylamino-pyrimidine Bcr-Abl inhibitor developed by Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patients with early stage disease. However, patients with advanced disease often become resistant to imatinib. The predominant form of this resistance is the development of mutations in the Bcr-Abl protein. These point mutations can be amino acid residues that make direct contact with imatinib or residues that do not allow Bcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation of the protein, both types of mutations prevent this inhibitor from binding. Several approaches have been taken to identify additional... 

BMS-354825, which has the generic name of dasatinib, entered Phase II clinical trials in December 2004 under the START (Src/Abl Tyrosine kinase inhibition Activity Research Trial) program [ 144-147]. Dosing was initiated at 70 mg twice daily with the option of increasing the dose to 90 or 100 mg or reducing the dose to 40 or 50 mg, depending on low response or toxicity. As part of the Phase I and II trials, patients were assessed for the presence of Bcr-Abl mutations prior to treatment with BMS-354825. In a study at UCLA,... 

Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 2001 7 228-34. 

Mechanism of Action Inhibits Bcr-Abl tyrosine kinase, an enzyme created by the Philadelphia chromosome abnormality found in patients with chronic myeloid leukemia (CML). Therapeutic Effect Suppresses tumor growth during the three stages of CML blast crisis, accelerated phase, and chronic phase. 

Abl tyrosine kinase also carries a myristinic acid residue as a membrane anchor. The complex structure is a distinctive feature of Abl tyrosine kinase (Fig. 8.15). The enzyme... 

Fig. 8.15. Domain structure of Abl tyrosine kinase. The functionally characterized domains of Abl tyrosine kinase are shown in hnear configuration. NTS, nuclear localization signal.

Like many other nonreceptor tyrosine kinases, Abl tyrosine kinase may be converted by mutations into a dominant oncoprotein and thus contribute to tumor formation. Abl tyrosine kinase was first discovered as the oncogene of murine Abelson leukemia virus. Chronic myelogenic leukemia in humans is cause by a chromosome translocation in which a fusion protein is created of Abl tyrosine kinase and a Bcr protein (c Chapter 14). The result is a greatly increased tyrosine kinase activity, to which a causal role in occurrence of this leukemia is attributed. 

The Crk protein was first discovered as the transforming principle of the retroviruses CTIO and ASV-1. Abl tyrosine kinase is under discussion as a binding partner of the SH3 domain of Crk (Feller et al., 1994). Possible binding partners of the SH2 domain have been described but their physiological function is unclear. 

Fig. 14.4. Formation of a hybrid oncoprotein, illustrated by translocation of the Abl tyrosine kinase. The gene for the Ser-spedfic protein kinase BCR is fused with a part of the c-abl gene in the process of the Philadelphia chromosome translocation. Fusion genes are produced on chromosome 22, coding for various fusion proteins. The most important fusion proteins are the p -and p -BCR-Abl hybrid proteins, which have increased Tyr kinase activity and an altered subcel-lular location.

Dorsey IF, Jove R, Kraker AJ et al. The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Ber-Abl tyrosine kinase and induees apoptosis of K562 leukemic cells. Cancer Res 2000 60 3127-3131. 

The enzymatic in vitro test of 1 against v-Abl-tyrosine kinase showed that it is a potent inhibitor with an IC50 = 38 nM, However, in cell, the IC50 is only 250 nM for the... 

---