2016
DOI: 10.1021/acs.jmedchem.5b01655
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Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K)

Abstract: The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.7) and PI3K (54 < IC50 (nM) < 341) in enzymatic inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated with inhibitors 9 and 14 in two tumor cell lines (A549, D54). Inhibitors pr… Show more

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Cited by 43 publications
(25 citation statements)
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“…SDC patients with tumors harboring mutations in PI3K pathway genes were reported to respond to PI3K/Akt/mTOR pathway inhibition [28,29]. While PIK3CA/HRAS mutated cases may be challenging to treat, development of dual-acting agents modulating MEK and PI3K signaling pathway has been in progress [30] suggesting that such treatment approach may eventually be explored in PIK3CA/HRAS mutated SDC cases.…”
Section: Discussionmentioning
confidence: 99%
“…SDC patients with tumors harboring mutations in PI3K pathway genes were reported to respond to PI3K/Akt/mTOR pathway inhibition [28,29]. While PIK3CA/HRAS mutated cases may be challenging to treat, development of dual-acting agents modulating MEK and PI3K signaling pathway has been in progress [30] suggesting that such treatment approach may eventually be explored in PIK3CA/HRAS mutated SDC cases.…”
Section: Discussionmentioning
confidence: 99%
“…[36][37][38][39] As part of this strategy, we recently reported the development of prototype smallmolecule MEK/PI3K bifunctional inhibitors for simultaneous targeting of these critical regulators of K-Ras-mediated transformation. 40,41 Bifunctional inhibitors were designed by covalent linking of structural analogs of the ATP-competitive pan-PI3K inhibitor ZSTK474 with analogs of the allosteric MEK inhibitors RO5126766 or PD0325901. One such bifunctional inhibitor, designated as ST-162, was formed by linkage of analogs of the PI3K inhibitor ZSTK474 and the MEK inhibitor PD0325901.…”
Section: Introductionmentioning
confidence: 99%
“…Several promising kinase inhibitors have been developed and advanced to clinical trials and practice over the past decades (12). As an approach towards multi-kinase targeting, a prototype bifunctional inhibitor ( ST-162 ; previously designated as compound 14) was designed based on computational docking studies using structural analogs of a potent PI3K inhibitor ZSTK474 and a MEK inhibitor PD0316684 (an analog of PD0325901) as templates with subsequent covalent linking of the active pharmacophores (13). Thus ST-162 exhibits bifunctional allosteric non-competitive MEK inhibition with simultaneous ATP competitive PI3K inhibition (13).…”
Section: Introductionmentioning
confidence: 99%