ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP PRSYM
    • 2016-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 104

Novel, Selective, Orally Active PAD4 Inhibitors for the Treatment of Autoimmune Disorders

Santosh Vishwakarma1, Gurulingappa Hallur 1, Himanshu Agrawal 1, Sharad Singh 1, Annasaheb Kalange 1, Seema Chikkur Gangadhar 1, Shuvranshu PraharaJ 1, Nafees Ahmad Quresh 1, Srikanth Kanagal Gopinath 1, Krishnakumar V 1, Sameer Mahmood 1, Rudresh G 1, Mohd Zainuddin 1, Rajendra Kristam 1, Ishtiyaque Ahmad 1, Ramachandraiah Gosu 1, Purra Buchi Reddy 1, N V S K Rao 1, Saloni Mehra 2, Jeyaraj D A 1, Takeshi Yura 1, Saravanakumar dhakshinamoorthy 1, Sriram Rajagopal 1, Dhanalakshmi Sivanandhan 3 and Sridharan Rajagopal 3, 1Jubilant Biosys, Bangalore, India, 2Jubilant Chemsys, Noida, India, 3Jubilant Therapeutics, Bangalore, India

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: autoimmune diseases, inflammatory bowel disease (IBD) and PAD, psoriasis, Rheumatoid arthritis (RA)

  • Tweet
  • Email
  • Print
Session Information

Date: Sunday, November 10, 2019

Session Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session (Sunday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Citrullination of proteins is catalyzed by a family of enzymes called the peptidylarginine deiminases (PADs). While the citrullinated proteins may have physiological roles in differentiation, development, cell death, and gene regulation, the pathological protein citrullination has been associated with a range of diseases including rheumatoid arthritis (RA), multiple sclerosis, alzheimer’s disease, psoriasis and cancer. Notably, the citrulinated proteins are of interest in the pathology in rheumatid arthritis and the citrullinated proteins were detected in the synovium of RA patients. One of the PAD enzymes, PAD4, was reported to be associated with RA and higher levels of PAD4 expression is reported in the synovium. PAD4 co-localizes with citrullinated proteins in the synovium. We hypothesized that inhibition of PAD4 would be beneficial in the treatment of RA and other autoimmune disorders. Our medicinal chemistry efforts have led to the identification and characterization of a series of novel and selective PAD4 inhibitors. The optimization and development of these inhibitors for a variety of autoimmune disorders is underway

Methods: A variety of approaches including the Structure Based Drug Design (SBDD) was employed to identify the hit series and to optimize the leads. The enzymatic activity of hPAD4, PAD1 and PAD2 was assessed using fluorescence based ammonia release assay. The level of citrullinated histones, which is a direct reflection of PAD4 activity, was measured in human neutrophils by ELISA. The mouse model of collagen-induced arthritis, oxazolone induced colitis and Imiquimod induced psoriasis were used to profile the lead compounds

Results: The lead compound PADi showed an IC50 of 190 nM against PAD4 in the biochemical assay. It was selective against PAD1 and PAD2 enzymes. In the human neutrophil-based assay, the compound showed significant inhibition of H3-Histone citrullination with an IC50 of 320 nM. PADi showed oral bioavailability of greater than 50% across species. Treatment with PADi showed significant improvement in disease index across the various animal models, with efficacies comparable to the standard of care. In Collagen Induced Arthritis and Oxazolone induced colitis models, 50 mpk (BID, P.O.) dose showed >70% reversal of clinical score, with no effect on body weight. The observed pharmacological benefit was accompanied by reduction of histone citrullination in tissue samples, indicating target engagement. In Imiquimod induced psoriasis model, application of 500 ug of compound topically showed a reduction of psoriatic index with a significant decrease in ear thickness and ear weight.

Conclusion: We have identified and optimized a few novel chemical series of PAD4 inhibitors. One of our lead compound, PADi, a selective PAD4 inhibitor, is efficacious in the disease model of arthritis, colitis by oral administration and in psoriasis by topical application. These results suggest that PAD4 inhibition could be a novel therapeutic strategy against unmet medical needs in autoimmune disorders. Further characterization and advanced pre-clinical studies of PADi is in progress.


Disclosure: S. Vishwakarma, None; G. Hallur, None; H. Agrawal, None; S. Singh, None; A. Kalange, None; S. Chikkur Gangadhar, None; S. PraharaJ, None; N. Ahmad Quresh, None; S. Kanagal Gopinath, None; K. V, None; S. Mahmood, None; R. G, None; M. Zainuddin, None; R. Kristam, None; I. Ahmad, None; R. Gosu, None; P. Buchi Reddy, None; N. Rao, None; S. Mehra, None; J. D A, None; T. Yura, None; S. dhakshinamoorthy, None; S. Rajagopal, None; D. Sivanandhan, None; S. Rajagopal, None.

To cite this abstract in AMA style:

Vishwakarma S, Hallur G, Agrawal H, Singh S, Kalange A, Chikkur Gangadhar S, PraharaJ S, Ahmad Quresh N, Kanagal Gopinath S, V K, Mahmood S, G R, Zainuddin M, Kristam R, Ahmad I, Gosu R, Buchi Reddy P, Rao N, Mehra S, D A J, Yura T, dhakshinamoorthy S, Rajagopal S, Sivanandhan D, Rajagopal S. Novel, Selective, Orally Active PAD4 Inhibitors for the Treatment of Autoimmune Disorders [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/novel-selective-orally-active-pad4-inhibitors-for-the-treatment-of-autoimmune-disorders/. Accessed August 12, 2022.
  • Tweet
  • Email
  • Print

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-selective-orally-active-pad4-inhibitors-for-the-treatment-of-autoimmune-disorders/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2022 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies