Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Bruton’s Tryosine Kinase (BTK) and Janus Kinase 3 (JAK3) are intimately involved in the signaling pathways regulating B cell and T cell functions. Perturbing either pathway leads to immune disorders and diseases such as rheumatoid arthritis (RA). The purpose of the study is to develop a small molecule inhibitor targeting BTK and JAK3
Methods: A novel small molecular inhibitor (AC0025) was rationally designed to selectively target BTK and JAK3 using computer-aided design. The inhibitory activity and selectivity were evaluated at enzymatic, molecular and cellular levels, and in rat CIA animal models. The pharmacological properties and safety were evaluated both in vitro AMEDT assays and in PK/PD/TOX animal models
Results: AC0025 inhibited BTK and JAK3 enzyme activity with IC50values of 0.9 nM for BTK and 0.1 nM for JAK3. AC0025 does not inhibit other JAK family members including JAK1 and JAK2 with the IC50 values of 10.5 µM and 2.16 µM, respectively. AC0025 covalently binds to Cys481 in BTK and Cys909 in JAK3 resulting in irreversible blockage of the ATP binding site of both kinases, and therefore silences BTK and JAK3 activities. The inhibitory potency and selectivity of AC0025 were further evaluated and confirmed in the cell lines either stably expressing BTK and JAK3, or activated by cytokines. In rat collagen-induced arthritis (CIA) model, AC0025 significantly reduced paw edema and the disease severity by oral administration. Pharmacologic properties of AC0025 as a therapeutic agent for RA were assessed using in vitro ADMET assays and PK/PD/Tox animal models.
Conclusion: AC0025 as a novel irreversible dual target inhibitor showed potent inhibitory activities against BTK and JAK3 and further studies to develop AC0025 as a therapeutic agent for RA are warranted.
Disclosure:
X. Xu,
ACEA Biosciences,
3;
L. Mao,
ACEA Biosciences Inc.,
3;
B. Xi,
ACEA Biosciences Inc.,
3;
X. Zhang,
ACEA Biosciences Inc.,
3;
C. Fang,
ACEA Biosciences Inc.,
3;
J. Liu,
ACEA Biosciences Inc.,
3;
W. Xu,
ACEA Biosciences Inc.,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluation-of-an-irreversible-dual-target-inhibitor-ac0025-of-brutons-tryosine-kinase-and-janus-kinase-3-as-a-therapeutic-agent-for-rheumatoid-arthritis/