Delving into the Latest Updates on CMG-002 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

CMG002

Target

PI3Ks x mTOR

Action

inhibitors

Mechanism

PI3K family inhibitors(Phosphatidylinositol 3-kinase family inhibitors), mTOR inhibitors(Serine/threonine-protein kinase mTOR inhibitors)

Therapeutic Areas

NeoplasmsEndocrinology and Metabolic DiseaseUrogenital Diseases

Active Indication-

Inactive Indication

Ovarian Cancer

Originator Organization

CMG Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

CHA University

CMG Pharmaceutical Co., Ltd.

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Sorafenib has been the only first systemic drug that improves survival of patients with advanced hepatocellular carcinoma (HCC). However, because the response rate of sorafenib is relatively low, novel therapeutic strategies are needed to improve survival in patients with HCC. This study investigated the effect of CMG002 alone and in combination with sorafenib on HCC in vitro and vivo.

METHODS:

The effect of a newly developed dual PI3K/mTOR inhibitor, CMG002, on the proliferation of Huh-7 and HepG2 HCC cells was investigated using the MTT assay. Western blotting was performed to assess phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. HepG2 cells were inoculated into mice, which were treated with vehicle, sorafenib, CMG002, and their combinations. Tumor cell proliferation and tumor angiogenesis were evaluated by immunohistochemical analysis of Ki-67 and CD31, respectively. Tumor cell apoptosis was detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Levels of key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways were evaluated by western blot analysis.

RESULTS:

The combination of sorafenib and CMG002 additively inhibited Huh-7 and HepG2 cell proliferation compared to single-agent treatment. Sorafenib and CMG002 as single agents differentially inhibited or activated key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. The combination of sorafenib and CMG002 inhibited all key enzymes in the two pathways. Treatment with CMG002 for 4 weeks alone and in combination with sorafenib strongly inhibited tumor growth. CMG002 inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, these effects were enhanced when CMG002 was combined with sorafenib.

CONCLUSIONS:

The combination of CMG002 and sorafenib significantly inhibited HCC cell proliferation and tumorigenesis by inhibiting the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. These findings suggest that CMG002 to be a potential novel candidate treatment for HCC.

01 Jun 2019·Molecules and cellsQ3 · BIOLOGY

Combination Therapy with a PI3K/mTOR Dual Inhibitor and Chloroquine Enhances Synergistic Apoptotic Cell Death in Epstein–Barr Virus-Infected Gastric Cancer Cells

Q3 · BIOLOGY

Article

Author: Hong, Sung Pyo ; Kruger, Annie J ; Jeong, Ju-Yeon ; Kim, Mi-Young ; Shin, Phil Kyung ; Hahm, Ki Baik ; Cho, Joo Young ; Kim, Sun Young ; Kim, Jaehee

We aimed to show that our newly developed PI3K/mTOR dual inhibitor, CMG002, when combined with an autophagy inhibitor, chloroquine (CQ), potently induces effective cancer cell death in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells, where both the PI3K/AKT/mTOR and autophagy pathways play important roles in disease pathogenesis.EBV- and mock-infected AGS and NUGC3 GC cell lines were treated with CMG002 +/- CQ.PI3K/AKT/mTOR signaling pathway mediators, cellular apoptosis and autophagy markers were confirmed by Western blot assay.Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay.CMG002 effectively blocked the PI3K/AKT/mTOR pathway by markedly decreasing phosphorylation of AKT and its downstream mediator S6.CMG002 induced G0/G1 cell cycle arrest and enhanced apoptotic cell death in AGS and NUGC3 cells, particularly EBV-infected cells compared with mock-infected cells, as confirmed by flow cytometric analyses and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays.The combination of CMG002 plus CQ synergistically increased apoptotic cell death in EBV-infected GC cell lines when compared with CMG002 alone (P < 0.05).Our results suggest that the new PI3K/mTOR dual inhibitor, CMG002, when used in combination with the autophagy inhibitor, CQ, provides enhanced therapeutic efficacy against EBVaGC.

01 Apr 2019·Gynecologic oncologyQ2 · MEDICINE

A novel PI3K/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer

Q2 · MEDICINE

Article

Author: An, Hee Jung ; Moon, Yong Wha ; Jeong, Ju Yeon ; Park, Kyung Soon ; Park, Ju Yeon ; Kim, Jin Sung ; Choi, Hye Joung ; Heo, Jin Hyung ; Kim, Se Hwa ; Cho, Hyeon Ju

OBJECTIVE:

Ovarian cancer is the leading cause of gynecologic-related mortality worldwide. Despite successful initial treatment, overall survival rates are very low because tumors develop resistance to chemotherapeutic drugs. The PI3K/mTOR pathway is a key signaling pathway involved in drug resistance of ovarian cancer cells. The aim of this study was to examine the effect of a newly developed PI3K/mTOR dual inhibitor, CMG002, on chemoresistant ovarian cancer cells.

METHODS:

We examined the effects of CMG002, and its synergistic effects when combined with paclitaxel or cisplatin, on cell viability, cell cycle arrest, and apoptosis of PTX-resistant SKpac17 or cisplatin-resistant A2780cis ovarian cancer cells in vitro. Western blot analysis was performed to assess expression of PI3K, p-mTOR, p-Akt, p-S6, Bim, and caspase-3. In vivo studies were carried out in a xenograft mouse model, followed by TUNEL and immunohistochemical staining of excised tumor tissue.

RESULTS:

CMG002 showed marked toxicity against chemoresistant ovarian cancer cells and re-sensitized these cells to chemotherapeutic agents by suppressing cell proliferation and inducing G1 cell cycle arrest and apoptosis. In vivo xenograft studies revealed that treatment with CMG002, either alone or in combination with paclitaxel or cisplatin, led to a marked reduction in tumor growth. CMG002 caused marked suppression of mTOR (Ser2448), Akt (Ser473), Akt (Thr308), and S6 (Ser235/236) phosphorylation, both in vitro and in vivo.

CONCLUSION:

Taken together, CMG002, a very potent PI3K/mTOR dual inhibitor, induced cytotoxicity in chemoresistant ovarian cancer cells, suggesting that this novel inhibitor might be a new therapeutic strategy for chemoresistant ovarian cancer.

100 Deals associated with CMG-002

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