JAK-STAT signaling is involved in a plethora of cytokine responses, many of which are involved in key cellular functions including homeostasis, wound healing and pathogen defense. Our approach has been to develop an allosteric inhibitor of TYK2 with no activity against any of the other members of the JAK family, or other kinases. This affords the specific inhibition of key pathogenic cytokines while sparing protective cytokines and minimizing potential side effects.
We achieve selectivity by designing small molecules that bind TYK2 allosterically at a site that is not conserved between other members of the JAK family and other kinases. In particular, we are targeting the catalytically inactive pseudokinase domain (JH2) of the protein, which stabilizes the catalytically active domain (JH1) in an inactive state in the absence of upstream cytokine signaling.
Our lead compound is projected to enter human clinical trials by the end of 2020. We have developed a portfolio of highly potent, selective and orally bioavailable small molecule inhibitors of TYK2 that minimize inhibition of TYK2 independent cytokine signaling, thereby allowing us to leverage the therapeutic potential of TYK2 inhibition while reducing the potential for adverse events associated with non-selective JAK inhibition.