Structural Mechanism of the Pan‐BCR‐ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance

@article{Zhou2011StructuralMO,
  title={Structural Mechanism of the Pan‐BCR‐ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance},
  author={Tianjun Zhou and Lois Commodore and Wei-sheng Huang and Yihan Wang and Mathew P. Thomas and Jeffrey A. Keats and Qihong Xu and Victor M. Rivera and William C. Shakespeare and Tim Clackson and David C. Dalgarno and Xiaotian Zhu},
  journal={Chemical Biology \& Drug Design},
  year={2011},
  volume={77}
}
The BCR‐ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation‐resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR‐ABL, including T315I, acting as a pan‐BCR‐ABL inhibitor. Here, we undertook a combined crystallographic and structure–activity relationship analysis on… 
BCR‐ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein
  • P. Buffa, C. Romano, +6 authors P. Vigneri
  • Biology, Medicine
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2014
TLDR
It is found that E286, M318, I360, and D381 are dispensable for ABL and BCR‐ABL protein stability but are critical for preserving catalytic activity, and these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.
Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation
TLDR
This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.
Recent advances in Bcr‐Abl tyrosine kinase inhibitors for overriding T315I mutation
TLDR
This review reports some of the major examples of third‐generation Bcr‐Abl inhibitors against the T315I mutation, which is resistant to the first‐ and second‐generation drugs currently approved, including imatinib, bosutinib, nilotinib, and dasatinib.
Identification of novel tyrosine kinase inhibitors for drug resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study
TLDR
Seven lead molecules are uncovered, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib, which are effective against CML.
Investigating allosteric regulation of ABL and BCR-ABL kinases: Implications for small molecule inhibitors
TLDR
The major focus of this study was to exploit the intramolecular SH3:linker interaction, to stabilize the downregulated kinase domain conformation of BCR-ABL and sensitize the kinase to both imatinib and GNF-2.
BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.
TLDR
These findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome, and in vitro resistance profiling was predictive of treatment outcomes in Ph(+) leukemia patients.
Ponatinib Is a Pan-BCR-ABL Kinase Inhibitor: MD Simulations and SIE Study
TLDR
The pan-BCR-ABL kinase inhibitor ponatinib exhibits potent activity against native, T315I, and all other clinically relevant mutants, and showed better inhibition than the previously known inhibitors.
Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.
TLDR
The first cocrystal structure of FLT3 with the TKI quizart inib is reported, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved Asp-Phe-Gly motif in the activation loop.
PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation
TLDR
PF-114 is a novel TKI developed with the specifications of targeting T315I and other resistance mutations in BCR/ABL; achieving a high selectivity to improve safety; and overcoming nonmutational resistance in Ph+ leukemias that significantly prolonged survival to a similar extent as ponatinib.
Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase
TLDR
Ponatinib inhibited the growth of RET+ and BCR-ABL+ cells with similar potency, while not affecting RET-negative cells, and is suggested that ponatinIB should be considered for the treatment ofRET+ tumors, in particular those expressing vandetanib-resistant V804M/L mutations.
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References

SHOWING 1-10 OF 31 REFERENCES
The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants.
TLDR
Analysis of the crystal structure of dasatinib-bound ABL kinase suggests that the increased binding affinity of d asatinib over imatinib is at least partially due to its ability to recognize multiple states of BCR-ABL.
Crystal Structure of the T315I Mutant of Abl Kinase
TLDR
The crystal structure of the kinase domain of the c‐Abl T315I mutant, as well as the wild‐type form, is presented, in complex with a pyrrolopyridine inhibitor, PPY‐A, to provide structural guidance for the design of clinically useful inhibitors of Bcr‐A Bl T 315I.
Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358.
TLDR
The cocrystal structure of T315I Abl Kinase domain provides the structural basis for this activity: the inhibitor associates with an active conformation of the kinase domain in the ATP-binding pocket and lacks the steric hindrance imposed by the substitution of threonine by isoleucine.
AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
TLDR
Design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants, and clinical evaluation ofAP24534 as a pan-BCR-ABl inhibitor for treatment of CML are reported.
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia.
TLDR
The potential of Abl kinase inhibitor combinations to induce stable responses even in advanced CML and interpret the emerging data in the context of CML pathogenesis is assessed.
In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.
TLDR
It is reported that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for allImatinib-resistant mutants tested, with the exception of T315I.
Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571).
The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia. Small molecule
Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
TLDR
BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinIB-resistant BCR-ABL mutants and illustrates how molecular insight into kinase inhibitors resistance can guide the design of second-generation targeted therapies.
Kinase domain mutations in cancer: implications for small molecule drug design strategies.
TLDR
It is appreciated that the current clinical arsenal of small molecule kinase inhibitors only contains the first weapons to be deployed in a long war against drug resistance mutations occurring in multiple kinases that target multiple cancers.
Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
TLDR
It is found that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined and a strategy for identifying inhibitors of STI-571 resistance is suggested.
...
1
2
3
4
...