Discovery of a novel class of AKT pleckstrin homology domain inhibitors

Daruka Mahadevan, Garth Powis, Eugene A Mash, Benjamin George, Vijay Gokhale, Shuxing Zhang, Kishore Shakalya, Lei Du-Cuny, Margareta Berggren, M. Ahad Ali, Umasish Jana, Nathan Ihle, Sylvestor Moses, Chloe Franklin, Satya Narayan, Nikhil Shirahatti, Emmanuelle Meuillet

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.

Original languageEnglish (US)
Pages (from-to)2621-2632
Number of pages12
JournalMolecular Cancer Therapeutics
Volume7
Issue number9
DOIs
StatePublished - 2008

Fingerprint

Insulin Receptor Substrate Proteins
3-Phosphoinositide-Dependent Protein Kinases
Computer Simulation
1-Phosphatidylinositol 4-Kinase
Surface Plasmon Resonance
Protein-Serine-Threonine Kinases
Pleckstrin Homology Domains
Neoplasms
Phospholipids
Cell Survival
Cell Proliferation
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Discovery of a novel class of AKT pleckstrin homology domain inhibitors. / Mahadevan, Daruka; Powis, Garth; Mash, Eugene A; George, Benjamin; Gokhale, Vijay; Zhang, Shuxing; Shakalya, Kishore; Du-Cuny, Lei; Berggren, Margareta; Ali, M. Ahad; Jana, Umasish; Ihle, Nathan; Moses, Sylvestor; Franklin, Chloe; Narayan, Satya; Shirahatti, Nikhil; Meuillet, Emmanuelle.

In: Molecular Cancer Therapeutics, Vol. 7, No. 9, 2008, p. 2621-2632.

Research output: Contribution to journalArticle

Mahadevan, D, Powis, G, Mash, EA, George, B, Gokhale, V, Zhang, S, Shakalya, K, Du-Cuny, L, Berggren, M, Ali, MA, Jana, U, Ihle, N, Moses, S, Franklin, C, Narayan, S, Shirahatti, N & Meuillet, E 2008, 'Discovery of a novel class of AKT pleckstrin homology domain inhibitors', Molecular Cancer Therapeutics, vol. 7, no. 9, pp. 2621-2632. https://doi.org/10.1158/1535-7163.MCT-07-2276
Mahadevan, Daruka ; Powis, Garth ; Mash, Eugene A ; George, Benjamin ; Gokhale, Vijay ; Zhang, Shuxing ; Shakalya, Kishore ; Du-Cuny, Lei ; Berggren, Margareta ; Ali, M. Ahad ; Jana, Umasish ; Ihle, Nathan ; Moses, Sylvestor ; Franklin, Chloe ; Narayan, Satya ; Shirahatti, Nikhil ; Meuillet, Emmanuelle. / Discovery of a novel class of AKT pleckstrin homology domain inhibitors. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 9. pp. 2621-2632.
@article{5defe636c9c344018cbd53b1f1ec346a,
title = "Discovery of a novel class of AKT pleckstrin homology domain inhibitors",
abstract = "AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with {"}in silico{"} calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.",
author = "Daruka Mahadevan and Garth Powis and Mash, {Eugene A} and Benjamin George and Vijay Gokhale and Shuxing Zhang and Kishore Shakalya and Lei Du-Cuny and Margareta Berggren and Ali, {M. Ahad} and Umasish Jana and Nathan Ihle and Sylvestor Moses and Chloe Franklin and Satya Narayan and Nikhil Shirahatti and Emmanuelle Meuillet",
year = "2008",
doi = "10.1158/1535-7163.MCT-07-2276",
language = "English (US)",
volume = "7",
pages = "2621--2632",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Discovery of a novel class of AKT pleckstrin homology domain inhibitors

AU - Mahadevan, Daruka

AU - Powis, Garth

AU - Mash, Eugene A

AU - George, Benjamin

AU - Gokhale, Vijay

AU - Zhang, Shuxing

AU - Shakalya, Kishore

AU - Du-Cuny, Lei

AU - Berggren, Margareta

AU - Ali, M. Ahad

AU - Jana, Umasish

AU - Ihle, Nathan

AU - Moses, Sylvestor

AU - Franklin, Chloe

AU - Narayan, Satya

AU - Shirahatti, Nikhil

AU - Meuillet, Emmanuelle

PY - 2008

Y1 - 2008

N2 - AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.

AB - AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT.

UR - http://www.scopus.com/inward/record.url?scp=54049116732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54049116732&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-07-2276

DO - 10.1158/1535-7163.MCT-07-2276

M3 - Article

VL - 7

SP - 2621

EP - 2632

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 9

ER -