2. Academic Validation
  3. Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis

Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis

  • J Med Chem. 2022 Jan 27;65(2):1206-1224. doi: 10.1021/acs.jmedchem.1c00926.
Brian T Hopkins 1,  Eris Bame 1,  Bekim Bajrami 1,  Cheryl Black 1,  Tonika Bohnert 1,  Carrie Boiselle 1,  Doug Burdette 1,  Jeremy C Burns 1,  Luisette Delva 1,  Douglas Donaldson 1,  Richard Grater 1,  Chungang Gu 1,  Marc Hoemberger 1,  Josh Johnson 1,  Sudarshan Kapadnis 1,  Kris King 1,  Mukesh Lulla 1,  Bin Ma 1,  Isaac Marx 1,  Tom Magee 1,  Robert Meissner 1,  Claire M Metrick 1,  Michael Mingueneau 1,  Paramasivam Murugan 1,  Kevin L Otipoby 1,  Evelyne Polack 1,  Urjana Poreci 1,  Robin Prince 1,  Allie M Roach 1,  Chris Rowbottom 1,  Joseph C Santoro 1,  Patricia Schroeder 1,  Hao Tang 1,  Eric Tien 1,  Fengmei Zhang 1,  Joseph Lyssikatos 1
Affiliations

Affiliation

  • 1 Research & Development, Biogen, Cambridge, Massachusetts 02142, United States.
PMID: 34734694 DOI: 10.1021/acs.jmedchem.1c00926
Abstract

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the Btk protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on Btk, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z