Delving into the Latest Updates on CGX-1321 with Synapse

主要目的：评价口服CGX1321在晚期胃肠道癌症（包括伴有Rspo2、Rspo3和RNF43基因突变的胃肠道癌症）患者的安全性和耐受性；确定剂量限制性毒性（DLT）及最大耐受剂量（MTD）和／或临床2期研究推荐剂量（RP2D）；进一步评价在证实有WNT信号通路上游基因（例如，Rspo2、Rspo3或RNF43）改变的组织学诊断的GI肿瘤受试者中，在MTD和／或RP2D剂量下，CGX1321的安全性和耐受性（扩大研究阶段）。

[Translation]

Primary objectives: To evaluate the safety and tolerability of oral CGX1321 in patients with advanced gastrointestinal cancer (including gastrointestinal cancer with Rspo2, Rspo3 and RNF43 gene mutations); to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) and/or the recommended dose (RP2D) for Phase 2 clinical studies; to further evaluate the safety and tolerability of CGX1321 at the MTD and/or RP2D doses in subjects with histologically diagnosed GI tumors with confirmed alterations in genes upstream of the WNT signaling pathway (e.g., Rspo2, Rspo3 or RNF43) (expansion study phase).

Start Date-

Sponsor / Collaborator

Guangzhou Curegenix Ltd.

NCT03507998

/ Unknown statusPhase 1

A Phase 1 Open-label Dose Escalation Study of CGX1321 in Subjects With Advanced Gastrointestinal Tumors

This is a multi-center, open label, repeat dose, Phase 1 study consisting of a Dose Escalation Phase and a Dose Expansion Phase to evaluate safety, pharmacokinetics, and clinical activity.

Start Date17 Jun 2017

Sponsor / Collaborator

Curegenix, Inc.

[+1]

NCT02675946

/ Unknown statusPhase 1

A Phase 1 Open-label Dose Escalation Study of CGX1321 in Subjects With Advanced Solid Tumors With Expansion in Advanced Gastrointestinal Tumors and Phase 1b Study of CGX1321 in Combination With Pembrolizumab in Subjects With Advanced Colorectal Cancer or in Combination With Encorafenib + Cetuximab in Subjects With BRAFV600E Mutated Advanced Colorectal Cancer

This is a multicenter, open-label study conducted in two phases: Phase 1 consisting of a CGX1321 Single Agent Dose Escalation Phase in solid tumors, CGX1321 Single Agent Dose Expansion Phase in GI tumors and Roll-over Cohort of CGX1321 and pembrolizumab in subjects who have progressed on single agent CGX1321 and Phase 1b consisting of CGX1321 in combination with pembrolizumab in colorectal tumors and CGX1321 in combination with encorafenib + cetuximab in BRAFV600E mutated colorectal tumors. Both phases are to evaluate safety, pharmacokinetics, and clinical activity.

Start Date01 Feb 2016

Sponsor / Collaborator

Curegenix, Inc.

[+1]

100 Clinical Results associated with CGX-1321

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100 Translational Medicine associated with CGX-1321

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100 Patents (Medical) associated with CGX-1321

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10

Literatures (Medical) associated with CGX-1321

01 Jun 2023·Acta Pharmacologica Sinica

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling

Article

Author: Shou, Jia-Ling ; Li, Liang-Peng ; Zeng, Chun-Yu ; An, Songzhu Michael ; Wu, Hao ; Wang, Wei Eric ; Tang, Lu-Xun ; Chen, Xiao-Kang ; He, Yan-Ji ; Zhang, Zong-Shu ; Wang, Xue-Mei ; Lu, Bing-Jun ; Yang, De-Zhong ; Wang, Liang ; Shi, Yu

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg^-1·d^-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of β-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.

01 Jan 2022·Gynecologic OncologyQ2 · MEDICINE

Sequential modulation of the Wnt/β-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance

Q2 · MEDICINE

Article

Author: Arend, Rebecca C ; Norian, Lyse A ; Scalise, Carly B ; Goldsberry, Whitney N ; Randall, Troy D ; Dholakia, Jhalak ; Novak, Lea ; Meza-Perez, Selene ; Katre, Ashwini A

BACKGROUNDProgress in immunotherapy use for gynecologic malignancies is hampered by poor tumor antigenicity and weak T cell infiltration of the tumor microenvironment (TME). Wnt/β-catenin pathway modulation demonstrated patient benefit in clinical trials as well as enhanced immune cell recruitment in preclinical studies. The purpose of this study was to characterize the pathways by which Wnt/β-catenin modulation facilitates a more immunotherapy-favorable TME.METHODSHuman tumor samples and in vivo patient-derived xenograft and syngeneic murine models were administered Wnt/β-catenin modulating agents DKN-01 and CGX-1321 individually or in sequence. Analytical methods included immunohistochemistry, flow cytometry, multiplex cytokine/chemokine array, and RNA sequencing.RESULTSDKK1 blockade via DKN-01 increased HLA/MHC expression in human and murine tissues, correlating with heightened expression of known MHC I regulators: NFkB, IL-1, LPS, and IFNy. PORCN inhibition via CGX-1321 increased production of T cell chemoattractant CXCL10, providing a mechanism for observed increases in intra-tumoral T cells. Diverse leukocyte recruitment was noted with elevations in B cells and macrophages, with increased tumor expression of population-specific chemokines. Sequential DKK1 blockade and PORCN inhibition decreased tumor burden as evidenced by reduced omental weights.CONCLUSIONSWnt/β-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy.

02 Nov 2021·Expert Opinion on Therapeutic PatentsQ2 · MEDICINE

Recent updates on Wnt signaling modulators: a patent review (2014-2020)

Q2 · MEDICINE

Review

Author: Patel, Bhumika D. ; Goswami, Vishalgiri G.

Introduction: Wnt signaling is a signal transduction pathway that plays a vital role in embryonic development and normal tissue preservation. Dysfunction of it gives rise to various diseases like cancer, Alzheimer's, metabolic and skeletal disorders, kidney and liver disease, etc. Thus, targeting Wnt pathway can be a potential approach to design and develop novel therapeutic classes.Areas covered: Authors provided an overview of Wnt modulators from 2014 to 2020. Different heterocyclic scaffolds and their pharmacology from a total of 104 PCT applications have been summarized.Expert opinion: The scientific community is working extensively to bring first in the class molecule to the market which targets Wnt pathway. Lorecivivint, Wnt inhibitor, for the treatment of knee Osteoarthritis and SM-04554, Wnt activator, for the treatment of androgenetic alopecia are currently under Phase III. Other molecules, LGK-974, RXC-004, ETC-159, CGX-1321, PRI-724, CWP-232291 and BC-2059 are also under different stages of clinical development for the treatment of cancer. Antibody based Wnt modulator, OTSA101-DTPA-90Y is currently under Phase I for the treatment of Relapsed or Refractory Synovial Sarcoma while OMP-18R5 is under Phase I for Metastatic Breast Cancer. Ongoing preclinical/clinical trials will define the role of the Wnt pathway in different therapeutic areas and open new opportunities.

100 Deals associated with CGX-1321

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Bile Duct Neoplasms	Phase 1	China	Guangzhou Curegenix Ltd.	18 May 2017
Esophageal Carcinoma	Phase 1	China	Guangzhou Curegenix Ltd.	18 May 2017
stomach adenocarcinoma	Phase 1	China	Guangzhou Curegenix Ltd.	18 May 2017
Adenocarcinoma of large intestine	Preclinical	China	Curegenix, Inc.	17 Jun 2017
Adenocarcinoma of large intestine	Preclinical	China	Guangzhou Curegenix Ltd.	17 Jun 2017
Pancreatic adenocarcinoma	Preclinical	China	Guangzhou Curegenix Ltd.	17 Jun 2017
Advanced Colorectal Adenocarcinoma	Preclinical	United States	Curegenix, Inc.	01 Feb 2016
Advanced Colorectal Adenocarcinoma	Preclinical	Taiwan Province	Curegenix, Inc.	01 Feb 2016
Advanced Malignant Solid Neoplasm	Preclinical	United States	Curegenix, Inc.	01 Feb 2016
Advanced Malignant Solid Neoplasm	Preclinical	Taiwan Province	Curegenix, Inc.	01 Feb 2016

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02675946 \| NCT03507998 (Keynote 596, ASCO 12023 \| ASCO 22023) Manual	Phase 1	Gastrointestinal Diseases	17	CGX1321±Pembrolizumab	(bafnqquuwk) = Across all cohorts, treatment was well tolerated with the majority of AEs being Grade 1/2 and not related to CGX1321, while Grade > 3 AEs related to CGX1321 were infrequent (~6%). yniuqfqovp (bulxpptccv ) View more	Positive	31 May 2023