Overcoming resistance against leukemia drug target

One of the most lethal diseases, leukemia is a cancer that starts in the stem cells of the bone marrow, which produce blood cells. Chronic myelogenous leukemia (CML) comprises about 20% of known leukemias in adults, and highly efficacious drugs have been developed against CML. However, in the advanced stage, 20% of patients relapse due to the resistance against the drugs inferred by spontaneous mutations. A collaborative effort by scientists from Harvard Medical School, Novartis Pharma, the Biozentrum and other research institutions has resulted in the discovery of a novel class of compounds, which overcomes this resistance by a new inhibition mechanism. This study has been published in Nature advance online publication.

CML is a haemotological disorder caused by an abnormal rearrangement of chromosomes, which results in the aberrant fusion protein Bcr-Abl. The unregulated tyrosine kinase activity of Bcr-Abl leads to the uncontrolled production of immature blood cells and thus leukemia. The clinically highly efficacious drugs Glivec and Tasigna (both Novartis) and Sprycel (BMS) have been developed against Bcr-Abl. These inhibitors block the kinase activity by competing against ATP. However, spontaneous mutations of Bcr-Abl in advanced-stage patients render these inhibitors ineffecient. This has stimulated the search for new inhibitors that can overcome this resistance.

Recently, GNF-2 has been discovered as a novel highly selective, non-ATP competitive inhibitor showing high potency against wild type Bcr-Abl and few of its ATP-binding site mutants. The new study shows that GNF-2 and the improved compound GNF-5 target the myristoyl-binding pocket of Bcr-Abl, which is remote from the ATP binding site. This new inhibition mechanism is evidenced by solution NMR data obtained by Navratna Vajpai in the group of Stephan Grzesiek at the Biozentrum together with scientists at Novartis Pharma. The result is corroborated by X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry.

The new allosteric inhibitors together with the ATP-competitive inhibitors cooperatively suppress the effect of resistant mutations, including the human Bcr-Abl T315I variant, which accounts for 20% of all variants. The new inhibitors promise exciting therapeutic opportunities by exploiting a new mechanism of action and may allow greater specificity in protein kinase inhibition with fewer off-target side effects.

NMR spectroscopy provides evidence for GNF-2 binding to the C-terminal myristate pocket of Abl. Adapted from JM Zhang et al. Nature 000, 1-6 (2010) doi:10.1038/nature08675

Source article

Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors. Jianming Zhang, Francisco J. Adrián, Wolfgang Jahnke, Sandra W. Cowan-Jacob, Allen G. Li, Roxana E. Iacob, Taebo Sim, John Powers, Christine Dierks, Fangxian Sun, Gui-Rong Guo, Qiang Ding, Barun Okram, Yongmun Choi, Amy Wojciechowski, Xianming Deng, Guoxun Liu, Gabriele Fendrich, André Strauss, Navratna Vajpai, Stephan Grzesiek, Tove Tuntland, Yi Liu, Badry Bursulaya, Mohammad Azam, Paul W. Manley, John R. Engen, George Q. Daley, Markus Warmuth & Nathanael S. Gray (2010).

Nature advance online publication 13 January 2010 | doi:10.1038/nature08675