2. Academic Validation
  3. Discovery of Reversible Covalent Bruton's Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib)

Discovery of Reversible Covalent Bruton's Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib)

  • J Med Chem. 2022 Apr 14;65(7):5300-5316. doi: 10.1021/acs.jmedchem.1c01170.
Timothy D Owens 1,  Ken A Brameld 1,  Erik J Verner 1,  Tony Ton 1,  Xiaoyan Li 1,  Jiang Zhu 1,  Mohammad R Masjedizadeh 1,  J Michael Bradshaw 1,  Ronald J Hill 1,  Danny Tam 1,  Angelina Bisconte 1,  Eun Ok Kim 1,  Michelle Francesco 1,  Yan Xing 1,  Jin Shu 1,  Dane Karr 1,  Jacob LaStant 1,  David Finkle 1,  Natalie Loewenstein 1,  Helena Haberstock-Debic 1,  Michael J Taylor 1,  Philip Nunn 1,  Claire L Langrish 1,  David M Goldstein 1
Affiliations

Affiliation

  • 1 Principia Biopharma, a Sanofi Company, 220 E Grand Ave, South San Francisco, California 94080, United States.
PMID: 35302767 DOI: 10.1021/acs.jmedchem.1c01170
Abstract

Bruton's tyrosine kinase (Btk), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved Btk inhibitors are irreversible covalent inhibitors and limited to oncology indications. Herein, we describe the design of covalent reversible Btk inhibitors and the discoveries of PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited potent and durable inhibition of Btk, in vivo efficacy in rodent arthritis models, and clinical efficacy in canine pemphigus foliaceus. Compound 11 has completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.

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