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Description

PF-06651600 is a newly discovered irreversible covalent JAK3-selective inhibitor. A high level of selectivity towards JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Preclinical data demonstrates that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. Based on the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata and vitiligo, the dual activity of PF06651600 towards JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention. PF-06651600 is in phase III clinical trial for the treatment of alopecia areata and in phase II clinical trial for the treatment of Crohn's disease, Rheumatoid arthritis, Ulcerative colitis and Vitiligo.

Originator

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.346 nM [IC50]
3779.0 nM [IC50]
1638.0 nM [IC50]
1507.0 nM [IC50]
PubMed

PubMed

TitleDatePubMed
Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.
2016 Dec 16
The European League Against Rheumatism (EULAR) - 17th Annual European Congress of Rheumatology (June 8-11, 2016 - London, UK).
2016 Jun
Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans.
2017 Mar 9
Jak3 deficiency blocks innate lymphoid cell development.
2018 Jan
Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials.
2018 Jul
PF-06651600, a Dual JAK3/TEC Family Kinase Inhibitor.
2019 Jun 21

Sample Use Guides

In Vivo Use Guide
Single administration - 30 mg/kg
Route of Administration: Oral
Substance Class
Concept
Record UNII
EAG4T1459K
Record Status Validated (UNII)
Record Version
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Name Type Language
RITLECITINIB TOSYLATE
Common Name English
RITLECITINIB TOSLATE
Common Name English
PF-06651600 TOSYLATE
Common Name English
Code System Code Type Description
CAS
2192215-81-7
Created by admin on Mon Oct 21 20:32:55 UTC 2019 , Edited by admin on Mon Oct 21 20:32:55 UTC 2019
PRIMARY
This is a non-substance concept
Related Record Type Details
ACTIVE MOIETY
This is a non-substance concept