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4ms
Isosteric Replacement of Sulfur to Selenium in a Thiosemicarbazone: Promotion of Zn(II) Complex Dissociation and Transmetalation to Augment Anticancer Efficacy. (PubMed, J Med Chem)
Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.
Journal
|
MB (Myoglobin)
|
COTI-2 • Triapine (3-AP)
10ms
Gastric cancer patient-derived organoids model for the therapeutic drug screening. (PubMed, Biochim Biophys Acta Gen Subj)
PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.
Journal
|
HER-2 (Human epidermal growth factor receptor 2)
|
napabucasin (BBI608) • COTI-2
12ms
Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure-Activity Relationships of the Novel PPP4pT Series. (PubMed, J Med Chem)
The PPP4pT:Fe(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe(III) complexes to the heme plane and its oxidation. The 1:1 Cu(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.
Journal
|
MB (Myoglobin)
|
COTI-2 • Triapine (3-AP)
over1year
Degradation of MYC by the mutant p53 reactivator drug, COTI-2 in breast cancer cells. (PubMed, Invest New Drugs)
Proteasome-mediated degradation was determined using the proteasome, inhibitor MG-132, while MYC half-life was measured using pulse chase experiments in the presence of cycloheximide. Co-treatment with COTI-2 and the MYC inhibitor, MYCi975 resulted in synergistic growth inhibition in all 4 mutant p53 cell lines investigated. The dual ability of COTI-2 to reactivate mutant p53 and degrade MYC should enable this compound to have broad application as an anticancer drug.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
COTI-2 • MG132 • MYCi975
over1year
Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants. (PubMed, Genes (Basel))
COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. Cisplatin synergy is consistent with P53's role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
cisplatin • gemcitabine • Koselugo (selumetinib) • doxorubicin hydrochloride • eprenetapopt (APR-246) • COTI-2 • Mustargen (mechlorethamine)
2years
Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance. (PubMed, Cancers (Basel))
Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe as an interesting new drug candidate with improved anticancer activity and resistance profile.
Journal
|
ABCC1 (ATP Binding Cassette Subfamily C Member 1)
|
COTI-2 • Triapine (3-AP)
2years
Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use? (PubMed, Cancers (Basel))
Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.
Review • Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
eprenetapopt (APR-246) • arsenic trioxide • rezatapopt (PC14586) • COTI-2
almost3years
Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments. (PubMed, Front Oncol)
First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.
Review • Journal
|
MDM2 (E3 ubiquitin protein ligase)
|
TP53 mutation • TP53 wild-type
|
bortezomib • eprenetapopt (APR-246) • COTI-2 • Nutlin-3 • CP-31398 • RITA
almost4years
COTI-2 induces cell apoptosis in pediatric acute lymphoblastic leukemia via upregulation of miR-203. (PubMed, Bioengineered)
Taken together, COTI-2 inhibits tumor growth in vitro and in vivo in Jurkat cells likely through miR-203-dependent mechanisms. COTI-2 may be a potential approach for T-ALL treatment.
Clinical • Journal
|
CASP3 (Caspase 3) • CASP9 (Caspase 9)
|
COTI-2
over4years
Targeting p53 for the treatment of cancer. (PubMed, Semin Cancer Biol)
Currently, multiple p53-MDM2/MDM4 antagonists are undergoing clinical trials, the most advanced being idasanutlin which is currently undergoing testing in a phase III clinical trial in patients with relapsed or refractory acute myeloid leukemia. Two mutant p53-reactivating compounds have progressed to clinical trials, i.e., APR-246 and COTI-2. Although promising data has emerged from the testing of both MDM2/MDM4 inhibitors and mutant p53 reactivating compounds in preclinical models, it is still unclear if these agents have clinical efficacy. However, should any of the compounds currently being evaluated in clinical trials be shown to have efficacy, it is likely to usher in a new era in cancer treatment, especially as p53 dysfunction is so prevalent in human cancers.
Review • Journal
|
MDM4 (The mouse double minute 4)
|
TP53 mutation • MDM2 mutation
|
eprenetapopt (APR-246) • idasanutlin (RG7388) • COTI-2