Delving into the Latest Updates on SRX-3207 with Synapse

Overview

Basic Info

Drug Type

Chemical drugs

Synonyms

Target

PI3K family x Syk

Mechanism

Phosphatidylinositol 3-kinase family inhibitors, Syk inhibitors(Spleen tyrosine kinase inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

SignalRx Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

SignalRx Pharmaceuticals, Inc.

University of California

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC29H29N7O3S

InChIKeyZZVOPDBZUNUMPR-UHFFFAOYSA-N

CAS Registry2254693-15-5

Author: Dinh, Huy Q. ; Joshi, Shweta ; Pham, Timothy V. ; Garlich, Joseph R. ; Tamayo, Pablo ; Durden, Donald L. ; Singh, Alok R. ; Skola, Dylan ; Sharabi, Andrew B. ; Glass, Christopher K. ; Zulcic, Muamera ; Shiang, Daniel ; Liu, Kevin X. ; Sanders, P. Dominick ; Morales, Guillermo A. ; Hedrick, Catherine C.

AbstractMacrophages (MΦ) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an MΦ Syk–PI3K axis drives polarization of immunosuppressive MΦs that establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacologic inhibition of Syk and/or PI3Kγ in MΦs promotes a proinflammatory MΦ phenotype, restores CD8+ T-cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow–derived macrophages (BMDM) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the “first-in-class” dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.

100 Deals associated with SRX-3207

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