Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor

Bioorganic & Medicinal Chemistry
Hisao HamaguchiTakayuki Inoue

Abstract

Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

Citations

Nov 19, 2019·Expert Opinion on Investigational Drugs·Jing WuChanghai Ding
Apr 30, 2020·Expert Opinion on Pharmacotherapy·Yoshiya Tanaka, Hiroyuki Izutsu
Jun 6, 2020·Immunological Medicine·Akio Morinobu
Dec 28, 2019·Journal of Crohn's & Colitis·Marc Ferrante, João Sabino
Jul 10, 2020·Modern Rheumatology·Yuko Kaneko
Sep 30, 2019·Topics in Current Chemistry·Shiyang ZhouGangliang Huang
Mar 16, 2019·Pharmaceuticals·Annie Mayence, Jean Jacques Vanden Eynde
May 7, 2019·Expert Review of Clinical Pharmacology·Qian QiuMingxing Guo
May 23, 2020·Clinical and Experimental Gastroenterology·Edoardo TronconeGiovanni Monteleone
Mar 18, 2020·Zeitschrift für Rheumatologie·Stephan Blüml
Dec 8, 2020·Chemico-biological Interactions·Iza Mirela Rodini Garcia-PrincivalTeresinha Gonçalves da Silva
Mar 21, 2021·Inflammatory Bowel Diseases·Isabel GarridoGuilherme Macedo
Mar 31, 2021·Journal of Medicinal Chemistry·Andrew C FlickChristopher J O'Donnell
Oct 9, 2021·Journal of Medicinal Chemistry·Cecilia C Ayala-AguileraAsier Unciti-Broceta
Dec 24, 2021·Chemical Biology & Drug Design·Shiyang Zhou, Gangliang Huang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.