Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036

Abstract

Summary Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for chronic myeloid leukemia (CML) patients. Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead “switch-control” inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1T315I-expressing cell lines, prolongs survival in mouse models of T315I-mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph+ leukemia.

Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

“…Due to its unique mechanism of action (binding to a "switch" pocket of the kinase domain that forces the kinase to adopt an inactive conformation), DCC-2036 has promise for the treatment of a broad range of TKI-resistant BCR-ABL mutations, including T315I. 43 The plant alkaloid omacetaxine is an investigational protein synthesis inhibitor that has demonstrated modest activity in a small phase 2 study of CML cases associated with the BCR-ABL/T315I mutation, 44 where 10% of CP patients with the T315I mutation have achieved CCyR. Omacetaxine appears to be associated with a high degree of myelosuppression.…”

Treatment of Chronic Myeloid Leukaemia: Current Practice and Future Prospects

“…Switch pocket inhibitors bind to amino acid residues that kinases use to undergo the conformational change from the inactive(closed) to the active(open) state and therefore they keep the kinase in the inactive conformation (Chan et al, 2011;Eide et al, 2011). An important structural feature of the Abl kinase is the presence of a series of hydrophobic residues that are stacked in a layer and help to stabilise the active conformation.…”

Molecular mechanisms for survival regulation of chronic myeloid leukemia stem cells

“…However, both inhibitors cannot inhibit the gatekeeper residue mutant T315I. With the development of structural biology and computational biology, an alternative strategy to target other BCR-ABL motifs that are remote from the kinase domain has been developed (Adrian et al, 2006;Chan et al, 2011;Zhang et al, 2011). This strategy would be unaffected by kinase mutations that confer the ability of TKI-resistance.…”

“…Additionally, using structure-based drug design, Chan et al developed an inhibitor, DCC-2036, which potently inhibits both unphosphorylated and phosphorylated forms of ABL1 by inducing an inactive conformation (Chan et al, 2011). This inhibitor exhibited effi cacy against the T315I mutant in vivo (Chan et al, 2011). The development of these inhibitors provides the possibility of overcoming TKI resistance caused by kinase mutations, including the T315I.…”

“…It can act cooperatively with an ATP competitive inhibitor to inhibit both wild type and T315I BCR-ABL activity (Zhang et al, 2011). Additionally, using structure-based drug design, Chan et al developed an inhibitor, DCC-2036, which potently inhibits both unphosphorylated and phosphorylated forms of ABL1 by inducing an inactive conformation (Chan et al, 2011). This inhibitor exhibited effi cacy against the T315I mutant in vivo (Chan et al, 2011).…”