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BIIB091 Sale

目录号 : GC63846

BIIB091 是一种高选择性可逆性 BTK 抑制剂,用于治疗自身免疫性疾病的。

BIIB091 Chemical Structure

Cas No.:2247614-80-6

规格 价格 库存 购买数量
5 mg
¥9,810.00
现货
10 mg
¥15,750.00
现货

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Sample solution is provided at 25 µL, 10mM.

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产品描述

BIIB091 is a highly selective, reversible BTK inhibitor for treating autoimmune diseases.

[1]. Hopkins BT, et al. Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis. J Med Chem. 2021 Nov 4.

Chemical Properties

Cas No. 2247614-80-6 SDF Download SDF
分子式 C28H34N10O2 分子量 542.64
溶解度 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 1.8428 mL 9.2142 mL 18.4284 mL
5 mM 0.3686 mL 1.8428 mL 3.6857 mL
10 mM 0.1843 mL 0.9214 mL 1.8428 mL
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Research Update

Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?

CNS Drugs 2022 Oct;36(10):1019-1030.PMID:36178589DOI:10.1007/s40263-022-00951-z.

In multiple sclerosis (MS) persisting disability can derive from acute relapses or, alternatively, from slow and steady deterioration, termed chronic progression. Emerging data suggest that the latter process occurs largely independent from relapse activity or development of new central nervous system (CNS) inflammatory lesions. Pathophysiologically, acute relapses develop as a consequence of de novo CNS infiltration of immune cells, while MS progression appears to be driven by a CNS-trapped inflammatory circuit between CNS-established hematopoietic cells as well as CNS-resident cells, such as microglia, astrocytes, and oligodendrocytes. Within the last decades, powerful therapies have been developed to control relapse activity in MS. All of these agents were primarily designed to systemically target the peripheral immune system and/or to prevent CNS infiltration of immune cells. Based on the above described dichotomy of MS pathophysiology, it is understandable that these agents only exert minor effects on progression and that novel targets within the CNS have to be utilized to control MS progression independent of relapse activity. In this regard, one promising strategy may be the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of B cells as well as myeloid cells, such as macrophages and microglia. In this review, we discuss where and to what extent BTK is involved in the immunological and molecular cascades driving MS progression. We furthermore summarize all mechanistic, preclinical, and clinical data on the various BTK inhibitors (evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, orelabrutinib, BIIB091) that are currently in development for treatment of MS, with a particular focus on the potential ability of either drug to control MS progression.

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.PMID:34734694DOI:10.1021/acs.jmedchem.1c00926.

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.

Next-generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells

Clin Transl Immunology 2021 Jun 14;10(6):e1295.PMID:34141433DOI:10.1002/cti2.1295.

Objectives: Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small-molecule inhibitor of BTK. Methods: BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial. Results: In vitro, BIIB091 potently inhibited BTK-dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC50s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell-targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long-lived complexes with BTK with t 1/2 of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC50s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B-cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B-cell activation, with an in vivo IC50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing. Conclusion: Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials.