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Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design.

Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB
Bioorg Med Chem 25 1481-1486 (2017)
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Cited: 17 times
EuropePMC logo PMID: 28129991

Abstract

PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW<300Da) for binding to PI3Kα by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.

Reviews - 5swr mentioned but not cited (1)

  1. Advances in chemical proteomic evaluation of lipid kinases-DAG kinases as a case study. Ware TB, Hsu KL. Curr Opin Chem Biol 65 101-108 (2021)

Articles - 5swr mentioned but not cited (2)

  1. Structural Features that Distinguish Inactive and Active PI3K Lipid Kinases. Zhang M, Jang H, Nussinov R. J Mol Biol 432 5849-5859 (2020)
  2. Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design. Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB. Bioorg Med Chem 25 1481-1486 (2017)


Reviews citing this publication (3)

  1. PI3K inhibitors: review and new strategies. Zhang M, Jang H, Nussinov R. Chem Sci 11 5855-5865 (2020)
  2. Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products. Iksen, Pothongsrisit S, Pongrakhananon V. Molecules 26 4100 (2021)
  3. Structural Determinants of Isoform Selectivity in PI3K Inhibitors. Miller MS, Thompson PE, Gabelli SB. Biomolecules 9 E82 (2019)

Articles citing this publication (11)

  1. The mechanism of PI3Kα activation at the atomic level. Zhang M, Jang H, Nussinov R. Chem Sci 10 3671-3680 (2019)
  2. Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications. Favalli N, Bassi G, Pellegrino C, Millul J, De Luca R, Cazzamalli S, Yang S, Trenner A, Mozaffari NL, Myburgh R, Moroglu M, Conway SJ, Sartori AA, Manz MG, Lerner RA, Vogt PK, Scheuermann J, Neri D. Nat Chem 13 540-548 (2021)
  3. Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors. Rathinaswamy MK, Gaieb Z, Fleming KD, Borsari C, Harris NJ, Moeller BE, Wymann MP, Amaro RE, Burke JE. Elife 10 e64691 (2021)
  4. Getting the Most Out of Your Crystals: Data Collection at the New High-Flux, Microfocus MX Beamlines at NSLS-II. Miller MS, Maheshwari S, Shi W, Gao Y, Chu N, Soares AS, Cole PA, Amzel LM, Fuchs MR, Jakoncic J, Gabelli SB. Molecules 24 E496 (2019)
  5. Discovering new PI3Kα inhibitors with a strategy of combining ligand-based and structure-based virtual screening. Yu M, Gu Q, Xu J. J Comput Aided Mol Des 32 347-361 (2018)
  6. Mapping of the FGF14:Nav1.6 complex interface reveals FLPK as a functionally active peptide modulating excitability. Singh AK, Wadsworth PA, Tapia CM, Aceto G, Ali SR, Chen H, D'Ascenzo M, Zhou J, Laezza F. Physiol Rep 8 e14505 (2020)
  7. Structural Perturbations due to Mutation (H1047R) in Phosphoinositide-3-kinase (PI3Kα) and Its Involvement in Oncogenesis: An in Silico Insight. Sharma J, Bhardwaj V, Purohit R. ACS Omega 4 15815-15823 (2019)
  8. Carbon dots enhance extracellular matrix secretion for dentin-pulp complex regeneration through PI3K/Akt/mTOR pathway-mediated activation of autophagy. Liu L, Li X, Bu W, Jin N, Meng Y, Wang Y, Wang D, Xu X, Zhou D, Sun H. Mater Today Bio 16 100344 (2022)
  9. Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies. Bhaskar BV, Rammohan A, Babu TM, Zheng GY, Chen W, Rajendra W, Zyryanov GV, Gu W. Sci Rep 11 12150 (2021)
  10. Class I PI3K Biology. Aytenfisu TY, Campbell HM, Chakrabarti M, Amzel LM, Gabelli SB. Curr Top Microbiol Immunol 436 3-49 (2022)
  11. Structural insights into the interaction of three Y-shaped ligands with PI3Kα. Zhou Q, Liu X, Neri D, Li W, Favalli N, Bassi G, Yang S, Yang D, Vogt PK, Wang MW. Proc Natl Acad Sci U S A 120 e2304071120 (2023)


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