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Protein kinase inhibitors
518 protein kinases regulate the activity of ca 30% of proteins by phosphorylation. In cellular signaling pathways many kinases are involved whose dysregulation has been implicated in cancer, Alzheimer’s disease, diabetes, epilepsy, Coffin-Lowry syndrome and other diseases. Inhibitors of protein kinase allow the targeting of the cause of cancer with minimum side-effects (as compared to chemotherapy). Highly successful cancer drugs Gleevec, Erbitux, Avastin, Iressa are protein kinase inhibitors. 20-30% of R&D spending of drug companies is allocated to protein kinase inhibitors.

Protein kinase inhibitors by Kinasera
Kinasera is a spin-off of the University of Tartu for commercialization of protein kinase inhibitors (PKI) and PKI-based bio-tools. Our developed inhibitor, ARC, is a low nanomolar bisubstrate analog-type inhibitor of basophilic PK. The Ki value of ARC towards cAMP-dependent PK (PKA) is close to 10 pM, which is more than 100 times lower than that value for most of the drugs currently on the market. ARC differs from the majority of inhibitors as it binds simultaneously to both ATP binding pocket and protein binding domain of the kinase. ARC is believed to be active towards 60-80 kinases, mostly basophilic PK.

Biochemical assays for the characterization of kinases and their inhibitors
ARCs can be labelled with fluorescent dyes The biochemical assays offered by Kinasera are intended for the characterization of ATP and protein substrate competitive inhibitors of protein kinases. The principle of the assays is competitive displacement of ARC-Photo probe from its complex with a protein kinase by an active site targeted inhibitor. The biochemical assays are also suitable for the titration of the active sites of the kinase. Read more...

Kinasera live cell assays for monitoring kinase activity in live cells
As ARC-Photo probes detect the active form of protein kinases, the assay is suitable for studying the activation mechanisms of protein kinases inside living cells, e. g., determining the potency of GPCR agonists and antagonist as the activity of PKA is modulated by G-protein (Gs and Gi) coupled receptors or direct activation of adenylate cyclases. Moreover, the assay can be exploited for the determination of cell penetrating properties and cellular activity of PKA inhibitors. Read more...

ARC-based assays can be developed into method to be used for measuring of kinase concentration, activity and location in cells. As changes in kinase activity can give rise to cancer or other diseases, such method can be developed into biomarker assays connected to certain diseases. Such biomarkers can be used for identifying patients with a certain disease, setting optimal drug doses, and measuring the effectiveness of the cure. Kinasera is currently carrying out research for the usage of ARC-LUm in cells and their lysates. A pilot study evaluationg the applicability of Kinasera-TRF probe based assay for the detection of extra cellular PKA (ECPKA) as cancer biomarker was concluded by Kinasera, University of Tartu and The Hematology-Oncology Clinic of Tartu University Hospital.

Kinasera has a license on a patent application for affinity chromatography and pull-down methods for purification and analysis of kinases.

Drug development
ARC could be active towards 60-80 basophilic kinases. Several basophilic kinases have been related to various diseases:
   AKT/PKB – several forms of cancers (breast, prostate, lung etc), type II diabetes;
   PKC – pituitary and thyroid tumors, lung, gastric and prostate cancers etc;
   ROCK – Alzheimer’s disease etc.

Currently Kinasera is developing selective ARC-type inhibitors thad could serve as potential drugs towards Pim and CK2. Kinasera is open for mutually beneficial collaborations in the field of the development of inhibitors of protein kinases and new bioanalytical methods.