Design of allele-specific inhibitors to probe protein kinase signaling

Bishop, Anthony C.; Shah, Kavita; Liu, Yi; Witucki, Laurie; Kung, Chi-yun; Shokat, Kevan M.

doi:10.1016/s0960-9822(98)70198-8

Cited by 216 publications

(202 citation statements)

References 39 publications

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“…One striking observation was the failure of the T315A allele to phosphorylate any classical ABL substrates in vitro. This same threonine to alanine substitution has been engineered into BCR-ABL (and other kinases) to render the enzyme uniquely sensitive to artificial ATP analogues, thereby allowing highly specific identification of downstream substrates and assessment of kinase dependence (29,31,43,44). Our results suggest that the signaling characteristics of these mutant enzymes should be carefully evaluated as they may not always closely mimic the wild-type allele.…”

Section: Discussionmentioning

confidence: 93%

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Skaggs

Gorre²,

Рывкин³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

128

140

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The success of targeting kinases in cancer with small molecule inhibitors has been tempered by the emergence of drug-resistant kinase domain mutations. In patients with chronic myeloid leukemia treated with ABL inhibitors, BCR-ABL kinase domain mutations are the principal mechanism of relapse. Certain mutations are occasionally detected before treatment, suggesting increased fitness relative to wild-type p210 BCR-ABL. We evaluated the oncogenicity of eight kinase inhibitor-resistant BCR-ABL mutants and found a spectrum of potencies greater or less than p210. Although most fitness alterations correlate with changes in kinase activity, this is not the case with the T315I BCR-ABL mutation that confers clinical resistance to all currently approved ABL kinase inhibitors. Through global phosphoproteome analysis, we identified a unique phosphosubstrate signature associated with each drug-resistant allele, including a shift in phosphorylation of two tyrosines (Tyr 253 and Tyr 257 ) in the ATP binding loop (P-loop) of BCR-ABL when Thr 315 is Ile or Ala. Mutational analysis of these tyrosines in the context of Thr 315 mutations demonstrates that the identity of the gatekeeper residue impacts oncogenicity by altered P-loop phosphorylation. Therefore, mutations that confer clinical resistance to kinase inhibitors can substantially alter kinase function and confer novel biological properties that may impact disease progression.chronic myelogenous leukemia ͉ kinase inhibitor resistance ͉ phosphoproteomics ͉ imatinib ͉ dasatinib P oint mutations in the kinase domain of BCR-ABL are primarily responsible for resistance to the ABL inhibitor imatinib (Gleevec) in chronic myelogenous leukemia (CML) patients. The majority of imatinib-resistant BCR-ABL point mutations (of Ͼ50 distinct examples now reported clinically) impair drug binding by restricting flexibility of the enzyme, precluding adoption of the inactive conformation required for imatinib binding (1-4). The second generation Abl inhibitor dasatinib is effective against imatinib-resistant CML because it binds the BCR-ABL kinase domain regardless of activation loop conformation (5-7). As a result, the number of BCR-ABL mutations capable of conferring resistance to dasatinib is small and is limited almost exclusively to direct contact sites (8, 9). One mutation, T315I, confers resistance to imatinib, dasatinib, and the imatinib-related compound nilotinib (AMN-107) (10, 11).Although discovered in the context of drug resistance, there is growing evidence that these mutations may confer other fitness advantages to BCR-ABL. First, the T315I and E255K mutants were each detected by our group in imatinib-naïve CML blast crisis patients by direct sequencing of total BCR-ABL cDNA and are therefore estimated to account for at least 20% of the CML tumor burden in these patients (1). In addition, these and other kinase domain mutations have been identified before treatment in CML patients using mutation-specific quantitative PCR (12-18). Furthermore, the analogous mutation to T315I in the...

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Section: Discussionmentioning

confidence: 93%

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Skaggs

Gorre²,

Рывкин³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

128

140

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“…Mutation of the gatekeeper residue decreased IC 50 fold meaning that the as-kinase was selectively inhibited. 24 In summary, the biochemical data characterising the interactions of WT and as-kinases with ATP and adenine-enlarged ATP analogues 90 (Fig. 2) form the basis of the idea that as-kinases are fully functional in cells; and that these kinases can either be selectively inhibited by providing base-enlarged ATP analogues that lack transferable phosphoryl groups, or can selectively transfer the -phosphate group of ATP analogues 5 carrying triphosphate groups onto their substrates.…”

Section: Chemical Genetics Of Protein Kinasesmentioning

confidence: 99%

Chemical approaches towards unravelling kinase-mediated signalling pathways

Hodgson

Schröder

2011

Chem. Soc. Rev.

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Citation for published item:rodgsonD hF F F nd hr¤ oderD wF @PHIIA 9ghemi l ppro hes tow rds unr velling kin seEmedi ted sign lling p thw ysF9D ghemi l so iety reviewsFD RH @QAF ppF IPIIEIPPQF Further information on publisher's website:httpXGGdxFdoiForgGIHFIHQWGgHg HHHPHiPublisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details.

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“…However, only Bbp1, Swe1, and Hsl1 can be phosphorylated by Cdc28 (budding yeast Cdk1) in vitro (Ubersax et al, 2003). In addition, acute inhibition of chemically sensitive Cdc28 (cdc28-as) activity with 1NM-PP1 (4-amino-1-tert-butyl-3-(1-napthylmethyl)pyrazolo [3,4-d]pyrimidine) (Bishop et al, 1998) only partially delocalized GFP-fused Cdc5 from the cytokinetic neckfilament and did not significantly influence GFP-Cdc5 localization at the SPB in nocodazole-arrested cells (J-E Park and KS Lee, unpublished data). These observations suggest that Cdc28-dependent phosphorylation events are not critically required for Cdc5 localizations in mitotic cells.…”

Section: Subcellular Localization and The Polo-box Domainmentioning

confidence: 99%

Yeast polo-like kinases: functionally conserved multitask mitotic regulators

et al. 2005

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The polo-like kinases (Plks) are a conserved subfamily of Ser/Thr protein kinases that play pivotal roles in regulating various cellular and biochemical events at multiple stages of M phase. Genetic and biochemical data revealed that both the budding yeast and the fission yeast polo kinase homologs (Cdc5 and Plo1, respectively) bear remarkable functional similarities with those in metazoan organisms, suggesting that the role of Plks is largely conserved throughout evolution. Thus, studies on Plks in genetically amenable lower eucaryotic organisms may yield valuable insights into the function of Plks in higher eucaryotic organisms. In this review, common properties and distinct functions of Cdc5 and Plo1 will be discussed and compared to properties and functions of Plks in higher eucaryotic organisms.

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Design of allele-specific inhibitors to probe protein kinase signaling

Cited by 216 publications

References 39 publications

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants

Chemical approaches towards unravelling kinase-mediated signalling pathways

Yeast polo-like kinases: functionally conserved multitask mitotic regulators

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