Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance.
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM(R)) BCR/ABL kinase variants. Both compounds potently inhibit most IM(R) variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM(R)-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.
Azam
Mohammad
M
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Nardi
Valentina
V
Shakespeare
William C
WC
Metcalf
Chester A
CA
Bohacek
Regine S
RS
Wang
Yihan
Y
Sundaramoorthi
Raji
R
Sliz
Piotr
P
Veach
Darren R
DR
Bornmann
William G
WG
Clarkson
Bayard
B
Dalgarno
David C
DC
Sawyer
Tomi K
TK
Daley
George Q
GQ
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides; D004351:Drug Resistance / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
C493107:AP23464; D001549:Benzamides; C473352:PD 166326; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases