Delving into the Latest Updates on AstraZeneca R&D Boston, Inc. with Synapse

Overview

Tags

Neoplasms

Endocrinology and Metabolic Disease

Infectious Diseases

Small molecule drug

Synthetic peptide

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Neoplasms	2
Endocrinology and Metabolic Disease	1
Infectious Diseases	1

Top 5 Drug Type	Count

Small molecule drug	3
Synthetic peptide	1

Top 5 Target	Count

KIFC1(kinesin family member C1)	1
CCKA(Cholecystokinin A receptor)	1
RSV L protein	1
TrkA x TrkB	1

Author: Throner, Scott ; Wu, Jiaquan ; Larsen, Nicholas A. ; Russell, Daniel ; Dakin, Leslie A. ; Howard, Tina ; Molina, Audrey ; Pendleton, Christopher S. ; Garcia-Arenas, Renee ; Pietenpol, Jennifer A. ; Ferguson, Andrew D. ; Chen, Huawei ; Godin, Robert ; Cheung, Tony ; Zheng, Xiaolan ; Cowen, Scott D. ; Keen, Nicholas

Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.

12 Mar 2015·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Efficacious Pseudomonas aeruginosa-Targeted Siderophore-Conjugated Monocarbams by Application of a Semi-mechanistic Pharmacokinetic/Pharmacodynamic Model

Q1 · MEDICINE

Article

Author: Rooney, Michael ; Tsai, Andy S. ; Bhagunde, Pratik R. ; Sha, Li ; Manjunatha, M. R. ; Quiroga, Olga ; Hatoum-Mokdad, Holia ; Zhao, Shannon X. ; Manyak, Erika L. ; Tan, Beesan ; Harris, Jennifer J. ; Murphy-Benenato, Kerry E. ; Chen, April ; Durand-Reville, Thomas F. ; Uria-Nickelsen, Maria ; Sylvester, Mark ; Ehmann, David E. ; Kim, Aryun ; Shapiro, Adam B. ; Zambrowski, Mark ; Jahic, Haris ; Galullo, Vincent ; Wu, Ye ; Mueller, John ; Patey, Sara ; Davis, Hajnalka E.

To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic β-lactams are stable to metallo-β-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 μg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.

Challenges in the discovery of new antibacterial agents

Author: Barbachyn, Michael

Bacterial resistance to currently available therapeutic agents continues to grow in scope and magnitude.Nevertheless, there has been a steady decline in the number of new antibacterial agents being approved by the various regulatory agencies.Some of the factors behind this unfortunate situation will be briefly discussed.The principal focus will be on challenges associated with finding novel antibacterial agents, especially those effective against Gram-neg. bacteria.The unique physicochem. properties of such agents, as well as the multivariate problem associated with reaching targets essential to the bacteria will be discussed.Finally, some thoughts on screening approaches aimed at identifying new antibacterial scaffolds will be shared.

100 Deals associated with AstraZeneca R&D Boston, Inc.

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100 Translational Medicine associated with AstraZeneca R&D Boston, Inc.

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Pipeline

Pipeline Snapshot as of 17 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

4

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

AZ-23 ( TrkA x TrkB )	Neoplasms More	Preclinical
AZ-27 ( RSV L protein )	Respiratory Syncytial Virus Infections More	Preclinical
AZ-82 ( KIFC1 )	Neoplasms More	Preclinical
AC170222 ( CCKA )	Obesity More	Preclinical