MEK1 inhibitors(Dual specificity mitogen-activated protein kinase kinase 1 inhibitors), PI3K family inhibitors(Phosphatidylinositol 3-kinase family inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

University of Michigan

Active Organization-

Inactive Organization

University of Michigan

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with ST-168

100 Translational Medicine associated with ST-168

100 Patents (Medical) associated with ST-168

Literatures (Medical) associated with ST-168

01 Jul 2018·Journal of Ocular Pharmacology and TherapeuticsQ4 · MEDICINE

Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors

Q4 · MEDICINE

Article

Author: Besirli, Cagri G. ; Welton, Amanda R. ; Galbán, Stefanie ; Pawar, Mercy ; Van Dort, Marcian E. ; Smith, Andrew ; Thurber, Greg M. ; Ross, Brian D.

PURPOSEST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168.METHODSPhotoreceptor cell line 661W and adult retinal pigment epithelium cell line ARPE-19 were treated with increasing concentrations of bifunctional inhibitors. Western blots, cell viability, and caspase activity assays were performed to evaluate MEK and PI3K inhibition and dose-dependent in vitro toxicity, and compared with monotherapy. In vivo toxicity profile was assessed by intravitreal injection of ST-162 and ST-168 in Dutch-Belted rabbits, followed by ocular examination and histological analysis of enucleated eyes.RESULTSRetinal cell lines treated with ST-162 or ST-168 exhibited dose-dependent inhibition of MEK and PI3K signaling. Compared with inhibition by monotherapies and their combinations, bifunctional inhibitors demonstrated reduced cell death and caspase activity. In vivo, both bifunctional inhibitors exhibited a more favorable toxicity profile when compared with MEK inhibitor PD0325901.CONCLUSIONSNovel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.

10 Aug 2017·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168)

Q3 · MEDICINE

Article

Author: Thurber, Greg M. ; Galbán, Stefanie ; Apfelbaum, April A. ; Luker, Gary D. ; Van Dort, Marcian E. ; Ross, Brian D. ; Hong, Hao ; Atangcho, Lydia ; Besirli, Cagri G. ; Nino, Charles A.

The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition.

100 Deals associated with ST-168

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	University of Michigan	25 Jul 2017

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