COTI-2, distinguished as a low-toxicity anticancer agent, is an orally bioavailable third-generation p53 activator that can reactivate mutant forms of p53 and concurrently inhibit the PI3K/AKT/mTOR signaling pathway. It has been shown to trigger apoptosis across various human tumor cell lines and possesses antitumor properties in head and neck squamous cell carcinoma (HNSCC) through both p53-dependent and independent mechanisms, effectively restoring mutant p53 to a wild-type structure[1].[2].[3].
体内研究
Furthermore, COTI-2 prominently suppresses tumor growth in HT-29 human colorectal tumor xenografts at a dosage of 10 mg/kg, effectively reducing tumor sizes at specific intervals post-treatment and extending the period for tumors to reach certain sizes. Remarkably, COTI-2 also significantly curtails tumor growth in the SHP-77 small cell lung cancer (SCLC) xenograft model with doses as minimal as 3 mg/kg. In treatments involving U87-MG tumors, COTI-2 not only shrinks tumor volumes at designated times after treatment but also prolongs the duration needed for the growth of U87-MG xenografts in nude mice[2].
体外研究
After 72 hours of treatment with COTI-2, there's a notable inhibition in the proliferation rates across all examined cell lines, including COLO-205, HCT-15, and SW620, demonstrating significant antiproliferative effects. COTI-2 also displays activity against several human glioblastoma cell lines, including U87-MG, SNB-19, SF-268, and SF-295, at relatively low concentrations. In SHP-77 cells treated with COTI-2 at approximate IC50 concentrations, early apoptosis is induced in 40 to 47% of the total cells[2].
COTI-2 细胞实验
Cell Line
Concentration
Treated Time
Description
References
human tumor primary culture 3-D explants
19-317 μM
72 h
measure drug-induced cell death by delayed-loss-of-membrane integrity and ATP content
Genes (Basel). 2023 Mar 19;14(3):747
T24 cells
0.5 and 1 μM
24, 48, 72, and 96 hr
To evaluate the inhibitory effect of COTI-2 on the proliferation of bladder cancer cells, results showed that COTI-2 significantly inhibited the proliferation of T24 cells.
Iran J Basic Med Sci. 2025;28(3):240-246
5637 cells
0.5 and 1 μM
24, 48, 72, and 96 hr
To evaluate the inhibitory effect of COTI-2 on the proliferation of bladder cancer cells, results showed that COTI-2 significantly inhibited the proliferation of 5637 cells.
Iran J Basic Med Sci. 2025;28(3):240-246
GLC-4/adr
0.48 μM
72 h
Evaluate the anticancer activity of COTI-2 on GLC-4/adr cells, showing an IC50 of 0.48 μM, exhibiting 17.3-fold resistance
J Med Chem. 2020 Nov 25;63(22):13719-13732
GLC-4
0.03 μM
72 h
Evaluate the anticancer activity of COTI-2 on GLC-4 cells, showing an IC50 of 0.03 μM
J Med Chem. 2020 Nov 25;63(22):13719-13732
SW480/Coti
9.51 μM
72 h
Evaluate the anticancer activity of COTI-2 on SW480/Coti cells, showing an IC50 of 9.51 μM, exhibiting 18.9-fold resistance
J Med Chem. 2020 Nov 25;63(22):13719-13732
SW480
0.56 μM
72 h
Evaluate the anticancer activity of COTI-2 on SW480 cells, showing an IC50 of 0.56 μM
J Med Chem. 2020 Nov 25;63(22):13719-13732
PCI13-wtp53
1.0 μmol/L
48 h
To assess the effect of COTI-2 on gene expression through RNA sequencing analysis, results showed that COTI-2 restored the DNA binding properties and transcriptional activity of the p53 mutant protein.
Clin Cancer Res. 2019 Sep 15;25(18):5650-5662
PCI13-G245D (mutant p53)
1.0 μmol/L
16 and 48 h
To evaluate the effect of COTI-2 on DNA damage response and replication stress markers, results showed that COTI-2 increased phosphorylation levels of γH2AX (S139) and Chk1 (S345), inducing apoptosis.
Clin Cancer Res. 2019 Sep 15;25(18):5650-5662
PCI13-pBabe (p53 null)
1.0 μmol/L
16 and 48 h
To evaluate the effect of COTI-2 on DNA damage response and replication stress markers, results showed that COTI-2 increased phosphorylation levels of γH2AX (S139) and Chk1 (S345), inducing apoptosis.
Clin Cancer Res. 2019 Sep 15;25(18):5650-5662
COTI-2 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Athymic nude mice
AN3-CA human endometrial tumor xenografts
Intravenously (i.v.)
25 mg/kg
COTI-2 3 times a week, paclitaxel for 5 consecutive days, until study end
Evaluate the combined therapeutic effect of COTI-2 with paclitaxel, results showed the combination was more effective than monotherapy with no overt toxicity
PLoS One. 2018 Jan 24;13(1):e0191766
BALB/c nude mice
T24 cell xenograft model
Intraperitoneal injection
3 mg/kg
Every other day for a total of eight injections
To evaluate the inhibitory effect of COTI-2 on bladder cancer growth in vivo, results showed that COTI-2 significantly inhibited tumor growth and induced apoptosis.
Iran J Basic Med Sci. 2025;28(3):240-246
Nude mice
Orthotopic mouse model of oral tongue cancer
Oral
75 mg/kg
To evaluate the antitumor effects of COTI-2 alone and in combination with cisplatin or radiation, results showed that COTI-2 significantly inhibited tumor growth and enhanced sensitivity to cisplatin and radiation.
Ovarian Cancer
... 展开 >> Fallopian Tube Cancer
Endometrial Cancer
Cervical Cancer
Peritoneal Cancer
Head and Neck Cancer
HNSCC 收起 <<
Phase 1
Recruiting
December 2018
United States, Illinois
... 展开 >>
Northwestern Memorial Hospital
Recruiting
Chicago, Illinois, United States
Contact: Wilberto Nieves-Neira, MD 312-472-4684
Principal Investigator: Wilberto Nieves-Neira, MD
United States, Texas
MD Anderson Cancer Centre
Recruiting
Houston, Texas, United States
Contact: Shannon Westin, MD 713-794-4314
Principal Investigator: Shannon Westin, MD 收起 <<
Ovarian Cancer
... 展开 >> Fallopian Tube Cancer
Endometrial Cancer
Cervical Cancer
Peritoneal Cancer
Head and Neck Cancer
HNSCC 收起 <<
Phase 1
Recruiting
December 2018
United States, Illinois
... 展开 >>
Northwestern Memorial Hospital
Recruiting
Chicago, Illinois, United States
Contact: Wilberto Nieves-Neira, MD 312-472-4684
Principal Investigator: Wilberto Nieves-Neira, MD
United States, Texas
MD Anderson Cancer Centre
Recruiting
Houston, Texas, United States
Contact: Shannon Westin, MD 713-794-4314
Principal Investigator: Shannon Westin, MD 收起 <<
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