Overview
This technology is a set of novel ATP-independent, extracellular signal-regulated kinase (ERK) inhibitors that have the potenital to provide specific targeting compared to existing ERK1/2 inhibitors. The lead ATP-independent ERK inhibitor candidates, interact with specific ERK substrate docking sites inhibiting substrate interactions and phosphate transfer. This precise targeting of key substrates in turn is predicted to reduce off target side effects and overcome the development of drug-resistance.
The novel ATP-independent ERK inhibitors were developed using computational and experimental methods to target ERK-substrate docking domains to selectively interfering with ERK1/2 regulation of substrate proteins. Currently available inhibitors of ERK1/2 are non-specific due to ATP competition, limiting their potential use as a therapeutic agents. The lead ATP-independent ERK inhibitors have been used to target ERK2 and has identify key structural groups that impart activity toward melanoma cancer cells containing mutant B-Raf and activated ERK1/2 signaling. Mutations in upstream regulators of the ERK1/2 proteins result in the constitutive activation of ERK1/2 that is characteristic to many drug resistant cancers. These compounds have the potential to prevent or overcome drug resistance associated with clinically relevant kinase inhibitors and may be used as a tool to elucidate the complex biological roles of ERK1/2 to develop novel anti-cancer therapeutics. These compounds have also been shown to enhance the antitumour activity of CHK2 inhibition in both a human diffuse large B-cell lymphoma (DLBCL) xenograft model as well as primary human DLBCL cells, suggesting inhibition of both ERK and CHK2 as a combinatorial therapy for human lympomas.
Applications
There is considerable interest in the development of inhibitors for the MAPK/ERK pathway members, which are estimated to be mutated in 30% of all cancers. Currently no FDA approved ERK inhibitors are available on the market though several are under clinical investigation (LY3214996; Eli Lilly, LTT462; Novartis, BVD-523; BioMed Discoveries). Available drugs that target the MAPK/ERK pathway are directed towards the upstream BRAF protein. The FDA has approved the BRAF inhibitors Vemurafenib (Zelboraf, Daiichi Sankyo, Genentech) and Dabrafenib (Tafinlar, GSK), with early results showing reduction in lesions of the bone, liver, and lungs. However, the majority of tumor regressions relapsed within 2-20 months after treatment with BRAF inhibitors. The majority of relapses resulted from acquired resistance associated with reactivation of the ERK signaling. These studies come in light of data that indicate a strong correlation with phospho-ERK expression in combination with Ras mutations in some late stage cancers (e.g. colorectal, pancreatic) and poor patient prognosis.
Advantages
-Novel targeting
-Reduced Side Effects
-Reduced Drug Resistance
Stage of Development
The results are supported by experimental evidence that includes interference of ERK substrate phosphorylation and inhibition of downstream ERK signaling functions.
(MB- 6/30/17)
R&D Required
Additional validation required.
Licensing Potential
UM seeks to develop and commercialize by an exclusive or non-exclusive license agreement and/or sponsored research with a company active in the area
Contact Info
Office of Technology Transfer
620 W Lexington St., 4th Floor
Baltimore, MD 21201
Email: [email protected]
Phone: (410) 706-2380