Kinases are regulatory proteins that control cell growth, differentiation and survival/death by transmitting biological signals from a cell's exterior environment to its nucleus, where genes that maintain health and genes that cause disease are turned on and off in response to these signals. Inhibitors of kinase, such as c-Jun N-terminal Kinase (JNK), are designed to bind to and block the activity of gene-regulating kinases, thereby inhibiting the ability of kinases to turn on specific genes that cause or contribute to disease. We have a major JNK drug discovery and development program, and we presently hold or own a significant portion of the intellectual property for kinase inhibitors for JNK and other important kinases, with an expanding and comprehensive intellectual property estate including multiple issued or pending patents.
Bruton's Trosine Kinase Inhibitor
AVL-292 is a novel, orally available, covalent drug that targets Bruton's tyrosine kinase (Btk).
Btk plays a critical role in the development and activation of B cells, and its inhibition will be of therapeutic significance in the treatment of both B cell-related hematological cancers (e.g. non-Hodgkin lymphoma (NHL) and B cell chronic lymphocytic leukemia (B-CLL), and autoimmune diseases (e.g. rheumatoid arthritis).
Our covalent approach to silencing the Btk protein has resulted in a product candidate with a potential best-in-class profile due to:
potent inhibition of Btk, B cell activation and B cell proliferation
To date, AVL-292 has demonstrated efficacy in animal models of rheumatoid arthritis and multiple sclerosis, diseases in which B cells play an important role.
Furthermore, in our Btk program, we have developed a companion covalent probe technology which can quantify occupancy of the drug target.
Because the covalent modification is persistent, the modified protein acts as a "built-in-biomarker" that can be isolated from cells and quantified. We have developed a molecularly-tagged version that we call a "covalent probe" that can be used to analyze a sample and determine how much of the target protein was bonded by the drug. The probe provides quantitative information regarding the extent of target silencing at the molecular level, and can thereby be correlated with the dose administered. This technique provides us with a path to design and execute more efficient and rational clinical development.