LA JOLLA, CA--(Marketwired - Oct 20, 2016) - ActivX Biosciences, Inc., a wholly-owned subsidiary of Kyorin Pharmaceutical Co., Ltd. (Tokyo), announces two reports published in high profile, peer-reviewed journals by ActivX® researchers and their collaborators that highlight the broad utility of the industry-leading KiNativ® kinase profiling platform.
One report, published in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1609019113), details the use of KiNativ® profiling for elucidating the role of the kinase activity of ERK5 in inflammatory signaling and proliferation. Numerous papers from others using both genetic means and a first-generation small molecule inhibitor had implicated ERK5's kinase function as a drug target for several diseases. These earlier reports have prompted academic groups and industry teams to pursue ERK5 kinase inhibitors for treatment of immune disorders and cancer.
ActivX scientists now report that they have generated specific ERK5 inhibitors devoid of the biological activity of earlier ERK5 inhibitors. Using KiNativ® target engagement studies in both lysates and intact cells, the ActivX team demonstrated that complete inhibition of ERK5 does not inhibit cell proliferation or immune response. The paper went on to show that the first generation ERK5 inhibitor also had a potent off-target activity against bromodomain(BRD)-containing proteins and that BRD inhibitory activity was the source of substantially all of the reported biological function for the compound. This study is definitive proof that the ERK5 kinase function is not a valid drug target in attenuating immune response and highlights the risks of using whole protein ablation genetic models or incompletely characterized small molecules for target validation.
The second report published in Biochemistry (doi: 10.1021/acs.biochem.6b00629) showcases the unique ability of the KiNativ® kinase profiling platform to profile kinases in their native cellular state. Specific CDK4/CDK6 inhibitors have been approved (palbociclib/Ibrance®) or designated by the FDA as Breakthrough Therapy (ribociclib, abemaciclib) for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. While these drugs have generally good clinical efficacy, there remains a need for additional biomarkers to predict patient response as well as to extend the use of these drugs beyond estrogen receptor (ER)-positive breast cancer.
By applying KiNativ® technology to cell lines known to be sensitive or resistant to CDK4/CDK6 inhibitors, ActivX scientists demonstrated that the cell killing efficacy of palbociclib was correlated with the ability of the drug to bind to CDK4/CDK6 (target engagement) in live cells. In cell lines sensitive to palbociclib, target engagement was high, whereas in resistant cells, CDK4/CDK6 showed no target engagement by the drug. In addition, indirect downstream targets of palbociclib affected in sensitive cells were unaffected in resistant cells. Such differences in target engagement and downstream effects are not distinguishable using standard recombinant kinase activity assays. Only within the complex environment of the cell are these properties revealed.
"These two reports demonstrate the broad range of scientific information that KiNativ® offers spanning target discovery and engagement, kinase selectivity profiling, and pathway analysis," explained John Kozarich, Chairman & President of ActivX. "These findings also suggest the possibility of applying the KiNativ® profiling to characterize patient tumors to predict the likelihood of drug response." ActivX is currently working with collaborators to incorporate KiNativ® profiling to new and ongoing clinical trials to optimize therapy based on personalized measures of target engagement.
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.
About Kyorin Pharmaceutical, Ltd.
Trusted among patients and professionals in the medical industry, KYORIN Pharmaceutical (http://www.kyorin-pharm.co.jp/en/) strives to be a company that contributes to the public health and is recognized as a one with social significance by improving its presence in specified therapeutic areas and through global discovery of novel drugs. KYORIN Pharmaceutical uses its franchise customer strategy in focusing on respiratory medicine, otolaryngology and urology, and concentrates resources on the core areas of respiratory, otolaryngological and urological diseases in developing ethical drugs.