The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile

Christopher A. Eide, Lauren T. Adrian, Jeffrey Tyner, Mary Mac Partlin, David J. Anderson, Scott C. Wise, Bryan D. Smith, Peter A. Petillo, Daniel L. Flynn, Michael W N Deininger, Thomas O'Hare, Brian Druker

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Abstract

Acquired point mutations within the BCR-ABL kinase domain represent a common mechanismof resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABLT315I mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds the switch control pocket involved in conformational regulation of the kinase domain. We evaluated the efficacy of DCC-2036 against BCRABLT315I and other mutants in cellular and biochemical assays and conducted cell-based mutagenesis screens. DCC-2036 inhibited autophosphorylation of ABL and ABLT315I enzymes, and this activity was consistent with selective efficacy against Ba/F3 cells expressing BCR-ABL (IC50: 19 nmol/L), BCR-ABLT315I (IC50: 63 nmol/L), and most kinase domain mutants. Ex vivo exposure ofCML cells from patients harboring BCR-ABL or BCR-ABLT315I to DCC-2036 revealed marked inhibition of colony formation and reduced phosphorylation of the direct BCR-ABL target CrkL. Cell-based mutagenesis screens identified a resistance profile for DCC-2036 centered around select Ploop mutations (G250E, Q252H, Y253H, E255K/V), although a concentration of 750 nmol/L DCC-2036 suppressed the emergence of all resistant clones. A decreased concentration of DCC-2036 (160 nmol/L) in dual combination with either nilotinib or dasatinib achieved the same zero outgrowth result. Further screens for resistance due to BCR-ABL compound mutations (two mutations in the same clone) identified BCR-ABLE255V / T315I as the most resistant mutant. Taken together, these findings support continued evaluation of DCC-2036 as an important new agent for treatment-refractory CML.

Original languageEnglish (US)
Pages (from-to)3189-3195
Number of pages7
JournalCancer Research
Volume71
Issue number9
DOIs
StatePublished - May 1 2011

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Mutagenesis
Mutation
Inhibitory Concentration 50
Clone Cells
DCC-2036
Point Mutation
Phosphorylation
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. / Eide, Christopher A.; Adrian, Lauren T.; Tyner, Jeffrey; Partlin, Mary Mac; Anderson, David J.; Wise, Scott C.; Smith, Bryan D.; Petillo, Peter A.; Flynn, Daniel L.; Deininger, Michael W N; O'Hare, Thomas; Druker, Brian.

In: Cancer Research, Vol. 71, No. 9, 01.05.2011, p. 3189-3195.

Research output: Contribution to journalArticle

Eide, CA, Adrian, LT, Tyner, J, Partlin, MM, Anderson, DJ, Wise, SC, Smith, BD, Petillo, PA, Flynn, DL, Deininger, MWN, O'Hare, T & Druker, B 2011, 'The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile', Cancer Research, vol. 71, no. 9, pp. 3189-3195. https://doi.org/10.1158/0008-5472.CAN-10-3224
Eide, Christopher A. ; Adrian, Lauren T. ; Tyner, Jeffrey ; Partlin, Mary Mac ; Anderson, David J. ; Wise, Scott C. ; Smith, Bryan D. ; Petillo, Peter A. ; Flynn, Daniel L. ; Deininger, Michael W N ; O'Hare, Thomas ; Druker, Brian. / The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. In: Cancer Research. 2011 ; Vol. 71, No. 9. pp. 3189-3195.
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abstract = "Acquired point mutations within the BCR-ABL kinase domain represent a common mechanismof resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABLT315I mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds the switch control pocket involved in conformational regulation of the kinase domain. We evaluated the efficacy of DCC-2036 against BCRABLT315I and other mutants in cellular and biochemical assays and conducted cell-based mutagenesis screens. DCC-2036 inhibited autophosphorylation of ABL and ABLT315I enzymes, and this activity was consistent with selective efficacy against Ba/F3 cells expressing BCR-ABL (IC50: 19 nmol/L), BCR-ABLT315I (IC50: 63 nmol/L), and most kinase domain mutants. Ex vivo exposure ofCML cells from patients harboring BCR-ABL or BCR-ABLT315I to DCC-2036 revealed marked inhibition of colony formation and reduced phosphorylation of the direct BCR-ABL target CrkL. Cell-based mutagenesis screens identified a resistance profile for DCC-2036 centered around select Ploop mutations (G250E, Q252H, Y253H, E255K/V), although a concentration of 750 nmol/L DCC-2036 suppressed the emergence of all resistant clones. A decreased concentration of DCC-2036 (160 nmol/L) in dual combination with either nilotinib or dasatinib achieved the same zero outgrowth result. Further screens for resistance due to BCR-ABL compound mutations (two mutations in the same clone) identified BCR-ABLE255V / T315I as the most resistant mutant. Taken together, these findings support continued evaluation of DCC-2036 as an important new agent for treatment-refractory CML.",
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AU - Anderson, David J.

AU - Wise, Scott C.

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