Delving into the Latest Updates on Milrebrutinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Docirbrutinib

+ [1]

Target

BTK C481S

Action

inhibitors

Mechanism

BTK C481S inhibitors(Bruton Tyrosine Kinase C481S inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases+ [2]

Active Indication

B-Cell Malignant NeoplasmChronic Lymphocytic LeukemiaFollicular Lymphoma+ [4]

Inactive Indication

Diffuse Large B-Cell LymphomaRecurrent Chronic Lymphoid LeukemiaRichter's syndrome

Originator Organization

Carna Biosciences, Inc.

Active Organization

Carna Biosciences, Inc.

Inactive Organization

Aptuit (Verona) Srl

BioNova Pharmaceuticals (Shanghai) Ltd.Startup

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC33H31FN6O3

InChIKeyLJODJUIHONTDMR-UHFFFAOYSA-N

CAS Registry2227211-00-7

Background:Bruton tyrosine kinase plays a key role in the survival, proliferation, activation and differentiation of B-lineage cells and the signaling of other receptors. It is overexpressed and constitutively active in the pathogenesis of B cell malignancies and has therefore become a target for therapeutic intervention. Some success has been achieved in the discovery of small molecules especially in the development of irreversible inhibitors. However, these inhibitors are punctuated by off target effects and have also become less effective in patients with mutations at Cys481. This motivated the search for inhibitors with improved efficacy and different binding modes.Methods:In this study we employed two new second generation inhibitors with different binding modes, Zanubrutinib and AS-1763, which are at various levels of clinical trials to highlight the molecular determinants in the therapeutic inhibition of BTK through computational studies.Results:This study revealed Zanubrutinib and AS-1763 exhibited free total binding energies of -98.76±4.63kcal/mol and -51.81±9.94kcal/mol respectively with Zanubrutinib engaging in peculiar hydrogen bond interactions with the hinge residues Glu475 and Met477 including Asn484, and Tyr485 whiles AS-1763 engaged Lys430, Asp539, and Arg525. These residues contributed the most towards the free total binding energy with energies above -1.0kcal/mol. The compounds further interacted differentially with other binding site residues through pi-alkyl, pi-cation, pi-anion, pi-pi-T-shaped, pi-sigma, pi-sulfur and pi-donor hydrogen bonds and Van der Waals interactions. These interactions resulted in differential fluctuations of the residues with consequential unfolding of the protein.Conclusion:Insights herein would be useful in guiding the discovery of more selective and potent small molecules.

14 Oct 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton’s Tyrosine Kinase

Q1 · MEDICINE

Article

Author: Furuichi, Hatsuo ; Irie, Takayuki ; Asami, Tokiko ; Kashimoto, Shigeki ; Kawahata, Wataru ; Sawa, Masaaki ; Kiyoi, Takao

Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.

01 Jul 1984·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Rifampicin curing of plasmids in Escherichia coli K12−rifampicin resistant host

Q3 · MEDICINE

Article

Author: Obaseiki-Ebor, E E

AbstractThe in-vitro rifampicin curing of R-plasmids JR225, BN102, BN106 and F’-plasmid F’lac+/R386 in Escherichia coli K12 rifampicin-resistant host J62–2 is described. The minimum rifampicin curing concentration and the frequency of curing of plasmids from the rifampicin-resistant host cell J62–2 and the isogenic rifampicin-sensitive J62–1 host cell were similar. However, rifampicin did not cure some test R-plasmids such as R222 and RP4 from rifampicin-resistant and rifampicin-sensitive host cells, indicating that it is the R-plasmid itself and not the host strain that determines rifampicin curing.

100 Deals associated with Milrebrutinib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diffuse Large B-Cell Lymphoma	Discovery	China	Carna Biosciences, Inc.	10 Nov 2022
Diffuse Large B-Cell Lymphoma	Discovery	China	Aptuit (Verona) Srl	10 Nov 2022
Diffuse Large B-Cell Lymphoma	Discovery	China	Carna Biosciences, Inc.	10 Nov 2022
Diffuse Large B-Cell Lymphoma	Discovery	China	Aptuit (Verona) Srl	10 Nov 2022
Diffuse Large B-Cell Lymphoma	Discovery	China	BioNova Pharmaceuticals (Shanghai) Ltd.Startup	10 Nov 2022
B-Cell Lymphoma	Discovery	China	BioNova Pharmaceuticals (Shanghai) Ltd.Startup	01 Jul 2022
Recurrent Chronic Lymphoid Leukemia	Discovery	China	BioNova Pharmaceuticals (Shanghai) Ltd.Startup	01 Jul 2022
Small Lymphocytic Lymphoma	Discovery	China	BioNova Pharmaceuticals (Shanghai) Ltd.Startup	01 Jul 2022
Chronic Lymphocytic Leukemia	Discovery	Netherlands	Carna Biosciences, Inc.	25 Aug 2021
Chronic Lymphocytic Leukemia	Discovery	Netherlands	Carna Biosciences, Inc.	25 Aug 2021