Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases

Abstract

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).

KLIFS: an overhaul after the first 5 years of supporting kinase research

“…Recently, a paper was published by Gerstenberger et al on the development of the selective TYK2 inhibitor PF-06826647 ( 34 ). In their paper, the authors describe having identified a determinant for the lower affinity of JAK inhibitors, such as tofacitinib, baricitinib and ruxolitinib, for TYK2 due to their pyrrolopyrimidine hinge-binding moiety.…”

From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

“…The POI is selected based on prior knowledge of its biology, such as an implicated or established role in disease pathology. This allows for a rational approach, where compounds can be designed in silico, using molecular modeling, followed by synthesis and biochemical evaluation of compound-target binding [11]. Alternatively, in cases where it is hard to predict the compound binding site, a library of compounds or fragments (see Section 2.3) can be screened against the purified protein target [12,13].…”

Safety and Pharmacokinetics of the Oral TYK2 Inhibitor PF‐06826647: A Phase I, Randomized, Double‐Blind, Placebo‐Controlled, Dose‐Escalation Study

“…In addition, preclinical studies demonstrated limited drug clearance via renal and biliary excretion in rats, and the major human clearance pathway for PF-06826647 was identified to be cytochrome P450 (CYP)-mediated (via CYP1A2, CYP2D6, and CYP3A) metabolism. 20 PF-06826647 has shown minimal inhibition of transporter proteins (i.e., MATE1, MRP1, MRP2, MRP3, sodium/Na+ taurocholate co-transporting polypeptide, OATP1B1, OATP1B3, and OCT2), with the exception of MATE2 inhibition. 20 In a phase I, first-in-human study (NCT03210961), we evaluated the safety, tolerability, and pharmacokinetics (PK) of PF-06826647 in healthy participants.…”

“…20 PF-06826647 has shown minimal inhibition of transporter proteins (i.e., MATE1, MRP1, MRP2, MRP3, sodium/Na+ taurocholate co-transporting polypeptide, OATP1B1, OATP1B3, and OCT2), with the exception of MATE2 inhibition. 20 In a phase I, first-in-human study (NCT03210961), we evaluated the safety, tolerability, and pharmacokinetics (PK) of PF-06826647 in healthy participants. In this report, we present safety, tolerability, and PK data for escalating single and multiple doses of PF-06826647.…”

“…However, based on preclinical exposure data in rats, using a spray‐dried dispersion formulation, it was expected to be moderately‐to‐well absorbed at the predicted clinically effective dose range in the clinic. In addition, preclinical studies demonstrated limited drug clearance via renal and biliary excretion in rats, and the major human clearance pathway for PF‐06826647 was identified to be cytochrome P450 (CYP)‐mediated (via CYP1A2, CYP2D6, and CYP3A) metabolism 20 . PF‐06826647 has shown minimal inhibition of transporter proteins (i.e., MATE1, MRP1, MRP2, MRP3, sodium/Na+ taurocholate co‐transporting polypeptide, OATP1B1, OATP1B3, and OCT2), with the exception of MATE2 inhibition 20 …”