Delving into the Latest Updates on Spebrutinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Spebrutinib (USAN/INN), Spebrutinib Besylate, AVL-292

+ [1]

Target

BTK

Action

inhibitors

Mechanism

BTK inhibitors(Tyrosine-protein kinase BTK inhibitors)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal DiseasesNeoplasms+ [3]

Active Indication-

Inactive Indication

B-cell lymphoma refractoryCD20 positive Follicular LymphomaDiffuse Large B-Cell Lymphoma+ [4]

Originator Organization

Celgene Corp.

Active Organization-

Inactive Organization

Celgene Corp.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC22H22FN5O3

InChIKeyKXBDTLQSDKGAEB-UHFFFAOYSA-N

CAS Registry1202757-89-8

CC-292 is an oral agent that is under clinical development for the treatment of rheumatoid arthritis an autoimmune inflammatory disorder.
This study will test the clinical effectiveness and safety of an orally (PO) administered dose of CC-292 compared to placebo in US female patients currently on background Methotrexate (MTX) with active Rheumatoid Arthritis (RA

Start Date01 Oct 2013

Sponsor / Collaborator

Celgene Corp.

100 Clinical Results associated with Spebrutinib

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100 Translational Medicine associated with Spebrutinib

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100 Patents (Medical) associated with Spebrutinib

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97

Literatures (Medical) associated with Spebrutinib

11 Apr 2025·ACS Pharmacology & Translational Science

Comprehensive Characterization of Bruton’s Tyrosine Kinase Inhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures

Review

Author: Servant, Nicole B. ; King, Alastair J. ; Jahic, Mirza ; Darragh, Antonia C. ; Lipner, Justin H. ; Hanna, Andrew M.

Uncovering a drug's mechanism of action and possible adverse effects are critical components in drug discovery and development. Moreover, it provides evidence for why some drugs prove more effective than others and how to design better drugs altogether. Here, we demonstrate the utility of a high-throughput in vitro screening platform along with a comprehensive panel to aid in the characterization of 15 Bruton's tyrosine kinase (BTK) inhibitors that are either approved by the FDA or presently under clinical evaluation. To compare the potency of these drugs, we measured the binding affinity of each to wild-type BTK as well as a clinically relevant resistance mutant of BTK (BTK C481S). In doing so, we discovered a considerable difference in the selectivity and potency of these BTK inhibitors to the wild-type and mutant proteins. Some of this potentially contributes to the adverse effects experienced by patients undergoing therapy using these drugs. Overall, noncovalent BTK inhibitors showed stronger potency for both the wild-type and mutant BTK when compared with that of covalent inhibitors, with the majority demonstrating a higher specificity and less off-target modulation. Additionally, we compared biological outcomes for four of these inhibitors in human cell-based models. As expected, we found different phenotypic profiles for each inhibitor. However, the two noncovalent inhibitors had fewer off-target biological effects when compared with the two covalent inhibitors. This and similar in-depth preclinical characterization of drug candidates can provide critical insights into the efficacy and mechanism of action of a compound that may affect its safety in a clinical setting.

15 Jan 2025·Journal of the American Chemical Society

Chemoselective Stabilized Triphenylphosphonium Probes for Capturing Reactive Carbonyl Species and Regenerating Covalent Inhibitors with Acrylamide Warheads in Cellulo

Article

Author: Chen, Ai-Lin ; Chang, Hsiao-Yu ; Wang, Tsung-Shing Andrew ; Lin, Zih-Jheng

Reactive carbonyl species (RCS) are important biomarkers of oxidative stress-related diseases because of their highly reactive electrophilic nature. Despite their potential as triggers for prodrug activation, selective labeling approaches for RCS remain limited. Here, we utilized triphenylphosphonium groups to chemoselectively capture RCS via an aqueous Wittig reaction, forming α,β-unsaturated carbonyls that enable further functionalization. We first designed native (light) and deuterated (heavy) probes to facilitate RCS metabolomic identification through distinct MS isotope patterns. This approach allowed us to capture and relatively quantify several endogenous RCS related to advanced lipoxidation/glycation end products (ALEs/AGEs). Second, we demonstrated that various endogenous RCS can trigger the in situ generation of acrylamide warheads of targeted covalent inhibitors (TCIs) with different substituents. These structural variations influence their protein binding profiles and consequently alter their cytotoxicity, which is beneficial for the development of inhibitor cocktails.

22 Feb 2024·Journal of medicinal chemistryQ1 · MEDICINE

Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases

Q1 · MEDICINE

Article

Author: Ouyang, Tianfeng ; Chen, Ting ; Wang, Qirui ; Yang, Zichao ; Zeng, Zhenhua ; Zhong, Guanghong ; Peng, Xiaopeng ; Wu, Yuhao ; Liu, Yao ; Ma, Zeli ; Chen, Zhen ; Huang, Junli ; Chen, Jianjun

Bruton's tyrosine kinase (BTK) is an attractive target in inflammatory and autoimmune diseases. However, the effectiveness of BTK inhibitors is limited by side effects and drug resistance. In this study, we report the development of novel BTK proteolysis targeting chimeras (PROTACs) with different classes of BTK-targeting ligands (e.g., spebrutinib) other than ibrutinib. Compound 23 was identified as a potent and fast BTK PROTAC degrader, exhibiting outstanding degradation potency and efficiency in Mino cells (DC_50, 4 h = 1.29 ± 0.3 nM, t_1/2, 20 nM = 0.59 ± 0.20 h). Furthermore, compound 23 forms a stable ternary complex, as confirmed by the HTRF assay. Notably, 23 down-regulated the BTK-PLCγ2-Ca²⁺-NFATc1 signaling pathway activated by RANKL, thus inhibiting osteoclastogenesis and attenuating alveolar bone resorption in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related inflammatory diseases, expanding the potential of BTK PROTACs.

1

News (Medical) associated with Spebrutinib

14 Aug 2023

·www.pharmaceutical-technology.com

ImPact enters partnership for pathologic myopia therapy development

Pathologic myopia, or myopic macular degeneration, is a severe eye disease. Credit: Serafino Mozzo / Shutterstock.com. Israeli biotech organisation ImPact Biotech has entered a research partnership with Maastricht University in the Netherlands to develop a therapy for arresting the progression of pathologic myopia or myopic macular degeneration (MMD), a severe eye disease. The organisation will work with two researchers from the university, associate professor Dr Mor Dickman and MERLN Institute associate professor Dr Vanessa LaPointe. Recommended Reports Reports LOA and PTSR Model - Radiprodil in Neurodegenerative Diseases GlobalData Reports LOA and PTSR Model - Spebrutinib Besylate in Follicular Lymphoma GlobalData View all Companies Intelligence Maastricht University Impact BioTech Ltd View all The parties will leverage the Padeliporfin vascular targeted photodynamic (VTP) therapy platform of ImPact for developing the treatment. Padeliporfin has received the European Medicines Agency’s approval for usage in low-risk prostate cancer patients. It is currently being evaluated in a Phase III clinical trial for treating low-grade upper tract urothelial carcinoma. The organisation also plans to commence further studies of Padeliporfin in patients with non-small cell lung cancer and pancreatic cancer. ImPact Biotech Research and Development global head Dr David Perry stated: “We look forward to collaborating with Maastricht University’s Drs LaPointe and Dickman on this important research collaboration to address the huge unmet medical need in progressive myopia while leveraging our Padeliporfin VTP technology to help patients afflicted with this highly debilitating condition. “Initial results with our Padeliporfin approach are very encouraging and we are looking forward to progressing it rapidly towards clinical research by growing our understanding of the disease and the potential interventions to change its course with the contribution of this collaboration.” The organisation is also partnering with research institutes and specialists in associated areas to analyse its platform’s potential to treat pathological myopia.

Phase 3Drug Approval

100 Deals associated with Spebrutinib

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External Link

KEGG	Wiki	ATC	Drug Bank
D10730	-	-	DB11764

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	United States	Celgene Corp.	01 Oct 2013
CD20 positive Follicular Lymphoma	Phase 1	United States	Celgene Corp.	18 Dec 2013
CD20 positive Follicular Lymphoma	Phase 1	Canada	Celgene Corp.	18 Dec 2013
CD20 positive Follicular Lymphoma	Phase 1	France	Celgene Corp.	18 Dec 2013
CD20 positive Follicular Lymphoma	Phase 1	Italy	Celgene Corp.	18 Dec 2013
Diffuse Large B-Cell Lymphoma	Phase 1	France	Celgene Corp.	01 Feb 2013
Recurrent Chronic Lymphoid Leukemia	Phase 1	United States	Celgene Corp.	01 Dec 2012
Recurrent Chronic Lymphoid Leukemia	Phase 1	Germany	Celgene Corp.	01 Dec 2012
Small Lymphocytic Lymphoma	Phase 1	United States	Celgene Corp.	01 Dec 2012
Small Lymphocytic Lymphoma	Phase 1	Germany	Celgene Corp.	01 Dec 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01975610 (Pubmed \| Rheumatol Ther)	Phase 2	Rheumatoid Arthritis	47	Spebrutinib 375 mg/day	kkkekjtiyw(mybvpgrqup) = xfqyvoashe itqyzcotjw (oypdphrhwm )	-	01 Mar 2020
				Placebo	kkkekjtiyw(mybvpgrqup) = hivefomzxc itqyzcotjw (oypdphrhwm )
NCT01975610 (ACR2016) Manual	Phase 2	Rheumatoid Arthritis	47	CC-292	iwjubnhtrh(ippiahzxdx) = xcepmxgnmc cxlmudsynr (jyyyciprvk )	Negative	14 Nov 2016
				Placebo	iwjubnhtrh(ippiahzxdx) = fslinurqie cxlmudsynr (jyyyciprvk )
ASCO2012	Phase 1	Chronic Lymphocytic Leukemia \| B-Cell Lymphoma	12	AVL-292 125 mg	uxfgceopjo(yhqbduonai) = mdazkrpkaq aflmccedri (gikqizhrhw, 50 - 212) View more	-	20 May 2012
				AVL-292 250 mg	uxfgceopjo(yhqbduonai) = drajplbzom aflmccedri (gikqizhrhw, 50 - 212) View more