Small Molecule Inhibition Targeting Kinases ERK5, PIkI, MPSI as a Therapeutic Strategy in Cardiovascular Disease, Prostate Cancer, and Glioblastoma

Project Overview

• For their critical role in cancer cell survival, kinases have successfully been exploited for their potential as therapeutic targets in many different types of cancers, such as pancreatic cancer, ovarian cancer, and colon cancer.
• Of special interest are targets such as Polo protein kinases (PIkI) as well as MPSI, ERK5 and TTK for their role in diseases including cardiovascular disease, prostate cancer, and glioblastoma. Their homology, however, challenges development of kinase-specific inhibitors to limit off-target inhibition. Therefore, there is a need for development of specific targets to a single kinase protein instead of multiple. 
• Dana-Farber scientists have created a portfolio of novel potent and selective inhibitors of Erk5, PlKl, and MPSI that are available for licensing.

Technology

The human kinome comprises a large family of structurally related protein kinases that play a central role in signal transduction and the regulation of diverse cellular processes. By catalysing phosphorylation, kinases act as molecular on/off switches mediating intracellular signalling through a cascade of events to modulate target protein biological function. Such phosphorylation events are typically triggered by extra-cellular stimuli, ultimately leading to cellular responses affecting various processes including activation of transcription factors, cell growth, migration, and differentiation. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems.

Researchers at Dana-Farber Cancer Institute are well-known for their expertise in kinase targeting and have developed a series of novel small molecules which have been shown to modulate and selectively inhibit the activity of at least one of MPSI, ERK5 and PIkI. These ATP-competitive kinase inhibitors demonstrated nanomolar concentration activity with IC50 values for inhibition of MPSI around 1.38 μM, while the in vitro ERK5 and PIkl binding assays reported Kd values in the nanomolar range, with ERK5 inhibitors ranging from 19550 nM, and PIkI ranging between 0.57-200 nM.

We have developed selective inhibitors which allow for a targeted therapeutic approach, and also pan-kinase inhibitors, which effectively inhibit resistance mutations that have emerged in prior therapies as well as suppress the initial emergence of mutations when used in earlier lines of therapy. Selectivity mitigates potential toxicity associated with kinase inhibition. 

Further Details: 

• Deng X, Yang Q, Kwiatkowski N, Sim T, McDermott U, Settleman JE, Lee JD, Gray NS. Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1. ACS Med Chem Lett. 2011 Mar 10;2(3):195-200. 
• Deng X, Elkins JM, Zhang J, Yang Q, Erazo T, Gomez N, Choi HG, Wang J, Dzamko N, Lee JD, Sim T, Kim N, Alessi DR, Lizcano JM, Knapp S, Gray NS. Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. Eur J Med Chem. 2013;70:758-67. 

Applications

Potential therapeutic applications for multiple kinase-associated cancers including pancreatic, ovarian or colon cancer.

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing this asset for further development into new oncology therapeutics.