Delving into the Latest Updates on Crossignal Therapeutics, Inc. with Synapse

Overview

Basic Info

Introduction

Crossignal Therapeutics is developing new generation of small molecule anti-cancer immunotherapies. They focus on the discovery of immune cell-expressed, tumor metabolic factors (TME)-targeted GPCRs (TMERs) and design drug candidates by testing their ability to inhibit critical pathways in TME-mediated cancer immune escape.

Tags

Neoplasms

Digestive System Disorders

Endocrinology and Metabolic Disease

Small molecule drug

Chemical drugs

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	7
Endocrinology and Metabolic Disease	1

Top 5 Drug Type	Count

Small molecule drug	6
Chemical drugs	1

Top 5 Target	Count

A1R x A2aR x A3R	1
GPR35(G-protein coupled receptor 35)	1

This is an FIH, multicenter, open-label, dose escalation and dose expansion study of CT3001, which will be conducted in 2 phases: Phase 1 and Phase 2a. Phase 1 will be a standard 3+3 dose escalation and dose finding study in patients with advanced solid tumors for whom there is no available therapy (or patients are not candidates for such therapy) for the assessment of DLTs at up to 6 dose levels of CT3001. Phase 2a is a dose expansion study to evaluate the preliminary efficacy of CT3001 in patients with advanced CRC or PDAC.

Start Date20 Sep 2024

Sponsor / Collaborator

Crossignal Therapeutics, Inc.

100 Clinical Results associated with Crossignal Therapeutics, Inc.

Login to view more data

0 Patents (Medical) associated with Crossignal Therapeutics, Inc.

Login to view more data

2

Literatures (Medical) associated with Crossignal Therapeutics, Inc.

05 Apr 2024·Cancer Research

Abstract LB426: Evidence for a role of GPR35 in IDO1-mediated tumor immune escape by regulating Hippo-YAP pathway

Author: Han, Sangdon ; Kim, Nam Hee ; He, Hongmei ; Chu, Zhi Liang

AbstractIDO1 is an immune checkpoint regulator and mediator of tumor immune evasion (1). The cellular and molecular mechanisms of IDO1-mediated immune suppression are not fully understood. We describe here that GPR35, the putative receptor for kynurenic acid (KYNA), a metabolite of IDO1-mediated tryptophan catabolism, couples to Hippo-YAP pathway. GPR35 activation, either by overexpression or by treatment with tryptophan metabolites resulted in Hippo inactivation and YAP-directed transcription via TEAD family of transcription factors. Recently, YAP is found to be essential for tumor immune escape. Yap1 deficiency in T-lineage-specific knockout mice, or by dosing a YAP inhibitor, impairs Treg formation and function, leading to tumor growth inhibition (2). YAP also plays an inhibitory role in CD8 T cell function, especially in activated CTL usually found in the TME [3,4]. Through medicinal chemistry design and a structure-vs-activity relationship study effort, we discovered a GPR35-selective inhibitor, here termed TMER1i. TMER1i potently blocks GPR35 in Hippo suppression and YAP activation. We showed that GPR35 is expressed in the T-cell lineage of the immune cells including naïve CD4 T cells, Treg and CD8 T cells. Treatment of purified human naïve CD4 T cells with anti-CD3/anti-CD28 under an IDO1+ TME-like culture condition in vitro induced a robust T cell activation and differentiation toward Treg phenotype, as shown previously using mouse naïve CD4 T cells by others (5). Importantly, TMER1i efficiently blocked the Treg differentiation under these conditions. When dosed in human-PBMC reconstituted NCG mice bearing HT29 tumors, TMER1i dose-dependently increased the infiltration of human CD8 T cells within tumors in a statistically significant manner, and a trending lower Treg cell infiltration, accompanied by a tumor growth inhibition. qPCR analysis of the HT29 tumors grown in the PBMC-NCG mice indicated that IDO1 was highly expressed in the tumors. These results indicated that GPR35 selective inhibitor TMER1i enhanced an anti-tumor immune activity in an IDO1+ tumor microenvironment. Taken together, these studies provided evidence for a role of GPR35 in mediating IDO1 immune suppression by regulating Hippo-YAP pathway in Treg and CTL cells in the immune system. Thus, GPR35 inhibitors have a potential to be novel immuno-therapeutic agents effective in treating patients with IDO1-positive tumors.Reference1.Munn, DH, and Mellor, AL. (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117:1147-11542.Ni, X. et al. Yap is essential for Treg-mediated suppression of antitumor Immunity. Cancer Discovery 2018; 8:1026-10433.Lebid, A. et al. (2020) YAP attenuates CD8 T cell-mediated anti-tumor response. Frontiers in Immunology 11:1-84.Stampouloglou, E. et al. (2020) YAP suppresses T-cell function and infiltration in the tumor microenvironment. PLoS Biol 18(1): e30005915.Fallarino, F. et al. (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor æ-chain and induce a regulatory phenotype in naïve T cells. J Immunol 176:6752-6761Citation Format: Hongmei He, Nam Hee Kim, Sangdon Han, Zhi Liang Chu. Evidence for a role of GPR35 in IDO1-mediated tumor immune escape by regulating Hippo-YAP pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB426.

05 Apr 2024·Cancer Research

Abstract LB166: Discovery of CT3021, a novel potent adenosine A2a/A2b/A1 receptor triple antagonist

Author: Han, Sandong ; He, Hongmei ; Kim, Nam Hee ; Chu, Zhi Liang

AbstractIn a CD73-positive tumor microenvironment (TME), ATP released from apoptotic tumor cells converts to adenosine, generating an adenosine-rich immunosuppressive environment. Adenosine activates G-protein coupled receptors expressed on immune cells to achieve immune suppression, with a mechanism of action involving 1) dampening antitumor effector cells (T eff and NK cells) via adenosine engagement on A2a receptor, (2) reducing dendritic cell antigen presentation and promoting MDSC differentiation by activating A2b and A2a receptors, and (3) inducing chemotactic migration of immature plasmacytoid dendritic cells to infiltrate tumor tissue via A1 receptor. Furthermore, A1 receptor expression in certain tumors mediates an adenosine-driven tumor cell proliferation, likely through A1 receptor Gi coupling to the Hippo-YAP signal transduction pathway. Thus, pharmacologic inhibition of A2a, A2b, and A1 receptors by a triple antagonist in the context of adenosine-rich TME may represent an attractive strategy to achieve a better outcome in treating solid tumors. We discovered and characterized a novel adenosine receptor antagonist CT3021. CT3021 exhibits high binding affinity to A2a, A2b, and A1, with a Ki value of 0.37 nM, 1.76 nM, and 1.26 nM, respectively, and is selective against the A3 receptor and other 84 pharmacologically and/or toxicologically relevant targets. Schild analysis demonstrated that CT3021 is a competitive antagonist with a calculated KB value of 0.18 nM on A2a receptor in a whole cell cAMP assay in transfected HEK293 cells. In functional antagonist assays, CT3021 maintains its high potency full antagonism under an adenosine-rich TME-like condition (10-100 µM adenosine) both in transfected HEK293 cells and in isolated human T lymphocytes. CT3021 has a high oral bioavailability, a limited CNS exposure, and a favorable ADME profile. CT3021 is well tolerated in rats after repeat dosing. Further toxicology and efficacy studies are underway to explore the potential of CT3021 as a best-in-class adenosine receptor antagonist immunotherapy for the treatment of CD73 positive and A1 receptor positive solid tumors.Citation Format: Sandong Han, Nam Hee Kim, Hongmei He, Zhi Liang Chu. Discovery of CT3021, a novel potent adenosine A2a/A2b/A1 receptor triple antagonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB166.

100 Deals associated with Crossignal Therapeutics, Inc.

Login to view more data

100 Translational Medicine associated with Crossignal Therapeutics, Inc.

Login to view more data

Corporation Tree

Boost your research with our corporation tree data.

login

or

view full example data

Boost your research with our corporation tree data.

Pipeline

Pipeline Snapshot as of 27 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

Discovery

2

3

Preclinical

Phase 2 Clinical

2

1

Other

Login to view more data

Current Projects

Drug(Targets)	Indications	Global Highest Phase

TMER1-i	Colonic Cancer More	Phase 2 Clinical
CT-3001 ( GPR35 )	Colorectal Cancer More	Phase 2 Clinical
Adenosine Blocker(Crossignal Therapeutics)	Solid tumor More	Preclinical
CT-3021 ( A1R x A2aR x A3R )	Neoplasms More	Preclinical
PD1/PD-L1 Blocker(Crossignal Therapeutics)	Solid tumor More	Preclinical