Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

Bioorganic & Medicinal Chemistry
Marcian E Van DortBrian D Ross

Abstract

The MAP kinase (Ras/MEK/ERK) and PI3K/Akt/mTOR oncogenic signaling pathways are central regulators of KRAS-mediated transformation. Molecular reciprocity between the Ras/MEK/ERK and PI3K/Akt/mTOR pathways provides cancer cells with the ability to evade treatment when targeting only one pathway with monotherapy. Multi-kinase targeting was explored through the development of a single bivalent chemical entity by covalent linking of high-affinity MEK and PI3K inhibitors. A prototype dual-acting agent (compound 8) designed using the PI3K inhibitor ZSTK474 and the Raf/MEK inhibitor RO5126766 as scaffolds displayed high in vitro inhibition of both PI3K (IC50=172nM) and MEK1 (IC50=473nM). Additionally, compound 8 demonstrated significant modulation of MEK and PI3K signaling pathway activity in human A549 human lung adenocarcinoma cells and pancreatic cancer cells (PANC-1) and also decreased cellular viability in these two cell lines.

References

Jan 24, 2009·Biochemistry·Thierry O FischmannVincent S Madison
Jul 25, 2009·Nature Reviews. Cancer·Jeffrey A Engelman
Jan 23, 2010·Nature Reviews. Cancer·Zachary A KnightKevan M Shokat
Jan 18, 2011·Expert Opinion on Investigational Drugs·Rina Barouch-Bentov, Karsten Sauer
Jul 23, 2011·Genes & Cancer·Esther Castellano, Julian Downward
Jul 5, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Maria Martinez-GarciaJean-Charles Soria
Sep 24, 2013·Cancer Treatment Reviews·Susan HeaveyKathy Gately

❮ Previous
Next ❯

Citations

Apr 21, 2016·Cancers·Daniel ZeitouniKirsten L Bryant
Oct 18, 2019·Journal of Cancer Research and Clinical Oncology·Xiaolin PengDexin Kong
Mar 20, 2020·Future Medicinal Chemistry·Shelly Pathania, Ravindra K Rawal
Apr 23, 2016·Oncotarget·Nobuo TsuchidaMichele Grieco
Jun 25, 2020·Drug Development Research·Parteek PrasherKamal Dua
Jan 27, 2016·World Journal of Gastroenterology : WJG·Tasuku Matsuoka, Masakazu Yashiro
May 1, 2018·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Andrew SmithCagri G Besirli
May 22, 2020·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Qiangqiang TaoHao Wang
Mar 12, 2020·Current Topics in Medicinal Chemistry·Hua Guo, Quan-Ping Diao
Aug 5, 2017·Molecular Cancer Therapeutics·Stefanie GalbánBrian D Ross
Dec 16, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Xiaogang YanFeng Wang
Mar 29, 2021·European Journal of Medicinal Chemistry·Chao WangPing Xu
Aug 4, 2021·Cancer Metastasis Reviews·Nianhong ChenPing Shi
Aug 25, 2017·ACS Medicinal Chemistry Letters·Marcian E Van DortBrian D Ross
Jun 17, 2019·Cells, Tissues, Organs·Miguel A OrtegaNatalio García-Honduvilla

❮ Previous
Next ❯

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.