In both publications, well-characterized kinase inhibitors were converted to degraders by conjugation with a thalidomide derivative that binds the Cereblon E3 ubiquitin ligase.
LA JOLLA, Calif., Jan. 19, 2018 (GLOBE NEWSWIRE) -- ActivX Biosciences, Inc., a wholly-owned subsidiary of Kyorin Pharmaceutical Co., Ltd. (Tokyo), announces two reports published in high profile, peer-reviewed journals by Professor Nathanael Gray at the Dana-Farber Cancer Institute, Jay Bradner of Novartis and their colleagues, in which the KiNativ platform was used to generate critical data supporting these studies.
Selective protein kinase degradation using heterobifunctional molecules consisting of separate binding elements for a kinase active site and an E3 ubiquitin ligase has emerged as a promising new modality for drug development. In contrast to the traditional approach of inhibiting the enzymatic activity of a kinase, once these bifunctional compounds bind to the targeted kinase, they recruit the ubiquitin-ligase which then can lead to quantitative loss of target enzyme through proteasome-dependent degradation. Several companies have been founded to develop such compounds, including Arvinas, C4 Therapeutics and Kymera.
In both publications, well-characterized kinase inhibitors were converted to degraders by conjugation with a thalidomide derivative that binds the Cereblon E3 ubiquitin ligase. In one report, published in Cell Chemical Biology (doi.org/10.1016/j.chembiol.2017.10.005), a promiscuous kinase inhibitor was converted to a degrader. Quantitative proteomics was used to identify 28 out of about 300 kinases that underwent degradation. The initial results were then used to guide the development of selective degraders for FLT3 and BTK. In the second report, published in Nature Chemical Biology (doi: 10.1038/nchembio.2538. Epub 2017 Dec 18) a CDK binding element was converted into a degrader, yielding a CDK9 selective degrader.
In both studies, the KiNativ platform was used to monitor the kinases that bound the degraders by measuring in-cell target engagement. Importantly, the number of kinases that bound the degraders was significantly higher than the number of kinases that underwent degradation, indicating that there is not a straightforward correlation between the affinity of a degrader for a kinase and its ability to degrade the kinase. Thus, the KiNativ platform provides a unique approach to monitoring the kinases capable of binding a degrader by interrogating those kinases that are in fact degraded compared to those that inhibit the targeted kinase but are not slated for degradation. This ActivX-proprietary technology yields important insights into the development of highly selective degraders and ultimately potential new medicines. Explained Professor Gray, “2018 will be the year we see an exponential increase in the number of small molecule degraders targeting a host of different protein targets. As the efficiency of degradation does not exclusively depend on typical parameters around target occupancy, proteomic technologies (both gene-family directed and global) that quantitatively measure protein abundance will be critical to evaluating the selectivity of new degrader molecules.”
ActivX provides technology solutions to over 90 pharmaceutical/biotech companies and academic institutions. To learn more about KiNativ® and its applications, go to www.kinativ.com or call ActivX Biosciences at 858 526-2515.
About ActivX Biosciences, Inc.
ActivX Biosciences, Inc. (www.activx.com) located in La Jolla, California, is a wholly-owned subsidiary of Tokyo-based Kyorin Pharmaceutical Co. Ltd, and has drug discovery and proteomics technology capabilities. The company applies proprietary chemical technologies and high-throughput protein analysis to the drug discovery and development process. By focusing on functional proteins, ActivX® addresses disease mechanisms directly, in contrast to approaches such as expression profiling, in which the measured analyte is several steps removed from the site of drug action. ActivX® and its partners are using ActivX’ s proprietary technology to address critical challenges in drug discovery, including selectivity profiling of candidate drug molecules across whole protein families in biological samples to guide their medicinal chemistry efforts, identifying novel drug targets and biomarkers, and characterizing off-target activities of candidate and established drugs to understand the basis of their efficacy and/or toxicity.
