Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site.
The ATP-competitive inhibitors dasatinib and nilotinib, which bind to catalytically different conformations of the Abl kinase domain, have recently been approved for the treatment of imatinib-resistant CML. These two new drugs, albeit very efficient against most of the imatinib-resistant mutants of Bcr-Abl, fail to effectively suppress the Bcr-Abl activity of the T315I (or gatekeeper) mutation. Generating new ATP site-binding drugs that target the T315I in Abl has been hampered, amongst others, by target selectivity, which is frequently an issue when developing ATP-competitive inhibitors. Recently, using an unbiased cellular screening approach, GNF-2, a non-ATP-competitive inhibitor, has been identified that demonstrates cellular activity against Bcr-Abl transformed cells. The exquisite selectivity of GNF-2 is due to the finding that it targets the myristate binding site located near the C-terminus of the Abl kinase domain, as demonstrated by genetic approaches, solution NMR and X-ray crystallography. GNF-2, like myristate, is able to induce and/or stabilize the clamped inactive conformation of Abl analogous to the SH2-Y527 interaction of Src. The molecular mechanism for allosteric inhibition by the GNF-2 inhibitor class, and the combined effects with ATP-competitive inhibitors such as nilotinib and imatinib on wild-type Abl and imatinib-resistant mutants, in particular the T315I gatekeeper mutant, are reviewed.
Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland. doriano.fabbro@novartis.com
Doriano
D
Fabbro
Paul W
PW
Manley
Wolfgang
W
Jahnke
Janis
J
Liebetanz
Alexandra
A
Szyttenholm
Gabriele
G
Fendrich
Andre
A
Strauss
Jianming
J
Zhang
Nathanael S
NS
Gray
Francisco
F
Adrian
Markus
M
Warmuth
Xavier
X
Pelle
Robert
R
Grotzfeld
Frederic
F
Berst
Andreas
A
Marzinzik
Sandra W
SW
Cowan-Jacob
Pascal
P
Furet
Jürgen
J
Mestan
D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D001549:Benzamides; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D020125:Mutation, Missense; D019814:Myristic Acid / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019814:Myristic Acid; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D016315:Proto-Oncogene Proteins c-abl