Delving into the Latest Updates on Bristol-Myers Squibb India Pvt Ltd. with Synapse

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Digestive System Disorders

Immune System Diseases

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Disease Domain	Count

Infectious Diseases	1
Immune System Diseases	1
Neoplasms	1

Top 5 Drug Type	Count

Small molecule drug	3

Top 5 Target	Count

TGF-β1(Transforming growth factor beta 1)	1
NS3(Hepatitis C virus (HCV) nonstructural protein 3)	1
RARγ x RORγt	1

AbstractGalectin-3 (Gal-3), a β-galactoside-binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139—a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis—is the most advanced small-molecule Gal-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high-resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) and V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. In addition, molecular dynamics simulations of both wild-type and mutant structures revealed the sustained favorable noncovalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3.

01 Jan 2021·Journal of Pharmacology and Experimental Therapeutics

Transporter Activity Changes in Nonalcoholic Steatohepatitis: Assessment with Plasma Coproporphyrin I and III

Article

Author: Deyati, Avisek ; Hadambar, Avinash Annasao ; Gautam, Shashyendra Singh ; Chatterjee, Sagnik ; Sankara Sivaprasad, L V J ; Mukherjee, Sambuddho ; Zhang, Yueping ; Naik, Tanvi ; Sinz, Michael ; Ramarao, Manjunath ; Murali, Bokka Venkata ; Gunti, Gowtham Raj ; Mariappan, T Thanga ; Basavanthappa, Sushma ; Shen, Hong ; Zinker, Bradley A ; Kuchibhotla, Vijaykumar

Expression and functional changes in the organic anion transporting polypeptide (OATP)-multidrug resistance-associated protein (MRP) axis of transporters are well reported in patients with nonalcoholic steatohepatitis (NASH). These changes can impact plasma and tissue disposition of endo- and exogenous compounds. The transporter alterations are often assessed by administration of a xenobiotic or by transporter proteomic analysis from liver biopsies. Using gene expression, proteomics, and endogenous biomarkers, we show that the gene expression and activity of OATP and MRP transporters are associated with disease progression and recovery in humans and in preclinical animal models of NASH. Decreased OATP and increased MRP3/4 gene expression in two cohorts of patients with steatosis and NASH, as well as gene and protein expression in multiple NASH rodent models, have been established. Coproporphyrin I and III (CP I and III) were established as substrates of MRP4. CP I plasma concentration increased significantly in four animal models of NASH, indicating the transporter changes. Up to a 60-fold increase in CP I plasma concentration was observed in the mouse bile duct-ligated model compared with sham controls. In the choline-deficient amino acid-defined high-fat diet (CDAHFD) model, CP I plasma concentrations increased by >3-fold compared with chow diet-fed mice. In contrast, CP III plasma concentrations remain unaltered in the CDAHFD model, although they increased in the other three NASH models. These results suggest that tracking CP I plasma concentrations can provide transporter modulation information at a functional level in NASH animal models and in patients. SIGNIFICANCE STATEMENT: Our analysis demonstrates that multidrug resistance-associated protein 4 (MRP4) transporter gene expression tracks with nonalcoholic steatohepatitis (NASH) progression and intervention in patients. Additionally, we show that coproporphyrin I and III (CP I and III) are substrates of MRP4. CP I plasma and liver concentrations increase in different diet- and surgery-induced rodent NASH models, likely explained by both gene- and protein-level changes in transporters. CP I and III are therefore potential plasma-based biomarkers that can track NASH progression in preclinical models and in humans.

100 Deals associated with Bristol-Myers Squibb India Pvt Ltd.

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100 Translational Medicine associated with Bristol-Myers Squibb India Pvt Ltd.

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Pipeline

Pipeline Snapshot as of 29 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

BMS-890068 ( NS3 )	Hepatitis C More	Preclinical
BMS-986313 ( RARγ x RORγt )	Psoriasis More	Preclinical
BMS-986260 ( TGF-β1 )	Colorectal Cancer More	Preclinical