COTI-2 / Cotinga Pharma - LARVOL DELTA

ABCC1 promotes GSH-dependent iron transport and resistance to Fe(II) and Cu(II) chelators. (PubMed, Biometals) - "Cells expressing ABCC1 displayed significant resistance to thiosemicarbazones (Dp44mT, COTI-2, DpC) in both their metal-free and metal-bound forms. Vesicular transport assays further demonstrated that ABCC1 actively transports the Fe-GSH complex, formed under physiological glutathione levels, indicating its role in regulating the labile iron pool and reducing intracellular iron toxicity. These findings underscore the importance of transporter-chelator interactions in shaping drug resistance and sensitivity and highlight the intricate roles of ABC transporters in modulating chelator activity."

Journal • Immunology • Oncology • ABCB1 • ABCC1 • ABCG2

Mechanism of acupuncture on cerebral ischemia-reperfusion injury via p53/SLC7A11/GPX4 signaling pathway in rat models (PubMed, Zhongguo Zhen Jiu) - "In the agonist group and acupuncture+agonist group, p53 agonist, COTI-2 was intraperitoneally injected (15 mg/kg), once daily for 7 consecutive days...In comparison with the acupuncture + agonist group, in the acupuncture group, the neurological deficit score increased (P<0.05), the percentage of cerebral infarction volume decreased (P<0.05), the pathological brain tissue damage was alleviated, the percentage of iron deposition in cortex and hippocampus decreased (P<0.01), the mitochondrial structure was normal in tendency; the levels of Fe2+ and MDA, as well as the mean fluorescence intensity of ROS were reduced (P<0.05), while the level of GSH rose (P<0.01); the mRNA and protein expression of GPX4 and SLC7411 was elevated (P<0.01, P<0.05), and that of p53 reduced (P<0.01, P<0.05). Xingnao Kaiqiao acupuncture can alleviate neurological damage in CIRI rats, which is obtained probably by inhibiting ferroptosis through p53/SLC7A11/GPX4 pathway."

Journal • Preclinical • Cardiovascular • CNS Disorders • Musculoskeletal Diseases • Orthopedics • Reperfusion Injury • GPX4 • SLC7A11

Disulfide-based 2-pyridyl-hydrazone prochelators induce iron deprivation and oxidative stress in ovarian cancer cells. (PubMed, J Biol Inorg Chem) - "We report the synthesis and biological evaluation of disulfide-based prochelators featuring a 2-pyridyl-hydrazone motif and resulting in a tridentate (S,N,N) donor set as found in several antiproliferative chelators (e.g., Triapine, Dp44mT, DpC, COTI-2). Accordingly, the preformed iron complex FePH3 also leads to apoptosis and iron dysregulation, and its toxicity is enhanced when the antioxidant capacity of the cells is impaired. The incorporation of the 2-pyridyl-hydrazone motif in disulfide-based prochelators therefore combines iron sequestration with pro-oxidant effects that could enhance the pharmacological profile of this chelation approach for cancer applications."

Journal • Oncology • Ovarian Cancer • Solid Tumor • TFRC

TP53 Mutation-Specific Dysregulation of Store-Operated Calcium Entry and Apoptotic Sensitivity in Triple-Negative Breast Cancer. (PubMed, Cancers (Basel)) - "TNBC cell lines harbouring frameshift and stop TP53 mutations exhibited reduced SOCE, lower CACNA1D expression, and resistance to thapsigargin-induced apoptosis compared to wild-type cells. This study identifies a novel link between TP53 mutation type and calcium signalling in TNBC. Reactivating mutant p53 with COTI-2 restores calcium-mediated apoptosis, supporting combination strategies targeting both TP53 dysfunction and calcium signalling."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7 • HER-2 • TP53

Electroacupuncture Attenuates Cerebral Ischemia-Reperfusion Injury by Inhibiting Ferroptosis via the p53/SLC7A11 Pathway. (PubMed, Clin Exp Pharmacol Physiol) - "Rats were randomly assigned to five experimental groups: Sham, MCAO/R, MCAO/R + COTI-2, MCAO/R + EA and MCAO/R + COTI-2 + EA...qRT-PCR and Western blot analyses revealed that EA downregulated p53 expression while upregulating SLC7A11 and GPX4 expression. In summary, ferroptosis was activated after CIRI, and EA ameliorated neurological deficits in cerebral ischemia models by modulating the p53/SLC7A11 axis to counteract oxidative stress-induced ferroptosis, ultimately providing neuroprotective benefits."

Journal • Cardiovascular • Reperfusion Injury • GPX4 • SLC7A11 • TP53

COTI-2 suppresses the malignancy of bladder cancer by inducing apoptosis via the AMPK-mTOR signaling pathway. (PubMed, Iran J Basic Med Sci) - "Our data suggest that COTI-2 effectively reduces the malignancy of BCa, probably by inducing apoptosis via the AMPK/mTOR signaling pathway. These data highlight the potential of COTI-2 as a therapeutic agent for the treatment of BCa."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

Tale of two mechanisms: Is the p53 modulator COTI-2 a zinc chaperone instead? (ACS-Fall 2024) - "Although the p53 protein remains “undruggable” two small molecules looking to reactivate misfolded p53 have entered clinical trials: APR-246 and COTI-2. The effects on p53 mutants will be discussed. These findings underscore the potential role of COTI-2 in regulating intracellular zinc levels, showing that COTI-2 continues to hold promise as a cancer therapeutic."

Colorectal Cancer • Gynecologic Cancers • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TP53

Mechanism of action of COTI-219 on RAS proteins (ACS-Fall 2024) - "This computational inquiry establishes a foundation for essential in vitro validation, providing insights into the targets and mechanism of COTI-219 within RAS proteins. Moving forward, we ware employing in-vitro validation studies based on these computational insights."

Oncology • HRAS • KRAS • NRAS

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 • Breast Cancer • Oncology • Solid Tumor • MB

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 • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2

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 • Oncology • MB

The impact of TP53 on calcium channel expression and regulation in triple-negative breast cancer (TNBC) (EACR 2023) - "Measuring store release with 4 uM thapsigargin (TG) in 0 mM physiological saline solution, and resulting store-operated calcium entry (SOCE) by addition of external CaCl2 (2 mM). In TP53 mutant cells, calcium entry was increased by COTI-2, indicating that TP53 reactivation enhances SOCE. This suggests calcium channels may be targeted to improve treatment sensitivity in TP53 mutant TNBC"

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CAV1 • TP53

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 • Breast Cancer • Oncology • Solid Tumor • TP53

The role of protein disulfide isomerase and copper in the paraptotic cell death of clinically investigated anticancer thiosemicarbazones (AACR 2023) - "Triapine is one of the best-known TSCs for anticancer therapy and is currently tested in a clinical phase III trial. To further improve the anticancer activity of TSCs, novel derivatives (such as DpC and COTI-2) have been developed and clinically investigated for their activity against solid tumors...The formation of the complex results in the interaction with thiol-containing proteins and subsequently in the disruption of the thiol-redox homeostasis, which leads to paraptotic cell death. Overall this work shed light on the paraptotic cell death and will be of interest for future clinical development of anticancer TSCs, as paraptosis is hypothesized to overcome apoptosis-resistance of cancer cells."

Clinical • Oncology • Solid Tumor

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 • Hematological Disorders • Hematological Malignancies • Oncology • Ovarian Cancer • Solid Tumor • TP53

Novel Strategies in High-Risk AML (SOHO 2019) - P1/2, P1b/2, P2, P3b; "However, single-agent decitabine does not lead to deep or durable remissions, and additional consolidation approaches must be identified and applied.28.30In initial studies, doublets with venetoclax appear to improve response rates (61%)31 vs. single agent decitabine (25-45%).25,26,28 Similar rates of infection were noted (∼30% neutropenic fevers) and 30-day mortality (∼7%), suggesting feasibility of hypomethylating/venetoclax doublets.25,27,31 Larger studies are underway to better characterize these combinations, and whether they lead to deeper molecular remissions or longer duration of remissions (NCT03404193, NCT03941964).Additional subsets of high-risk patients may be approached with alternative targeted strategies. There is much interest in hypomethylating doublets using FLT3 inhibitors.32 Sorafenib and midostaurin have been examined. On-going studies are examining gilteritinib doublets. Ivosidenib and enasidenib have just recently been approved for..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Gain of Function (GOF) Mutant p53 in Cancer-Current Therapeutic Approaches. (PubMed, Int J Mol Sci) - "Several of them, APR-246, COTI-2, SAHA, and PEITC, were approved for clinical trials. This review focuses on these novel therapeutic opportunities, their mechanisms of action, and their significance for potential medical application."

Journal • Review • Oncology • TP53

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 • Oncology • Solid Tumor • ABCC1

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."

Journal • Review • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • TP53

Insights into the multi-faceted role of Pioneer transcription factors in glioma formation and progression with targeting options. (PubMed, Biochim Biophys Acta Rev Cancer) - "Herein, we describe the main structural characteristics and functional mechanisms of pioneer TFs, focusing on their central role in the pathogenesis and progression of gliomas. We further highlight the current treatment options ranging from natural agents (oleanolic acid) to a variety of chemical compounds (APR-246, COTI-2) and discuss potential delivery systems, including nanoparticles, viral vectors, and intracellular protein delivery techniques."

Journal • Review • Brain Cancer • Glioma • Oncology • Solid Tumor

Drugging the undruggable-targeting P53: A comparative analysis of APR-246 and coti-2 in human tumor primary culture explants. (ASCO 2022) - "COTI activity correlated with Nitrogen Mustard and Alpelisib (PIK3CA) while APR activity correlated with Doxorubicin and Everolimus. P53’s function as the “guardian of the genome” is consistent with our findings that many cytotoxic and targeted agents that induce cell death reveal correlations with APR and COTI. While APR affects the structural conformation of P53, COTI may function downstream via oxidative, metabolic or other stress responses. The correlation coefficient for APR vs COTI at 0.146 (NS) suggests distinct mechanisms of action."

Gynecologic Cancers • Hematological Disorders • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA • TP53

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."

Journal • Review • Head and Neck Cancer • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MDM2

Liposomal formulations of anticancer copper(II) thiosemicarbazone complexes. (PubMed, Dalton Trans) - "α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu-triapine. Taken together, the here presented nanoformulation of Cu-triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones."

Journal • Oncology • Solid Tumor

Safety and early efficacy signals for COTI-2, an orally available small molecule targeting p53, in a phase I trial of recurrent gynecologic cancer (AACR 2018) - P1; "Eight patients had received one or more bevacizumab combinations, and two had received immune checkpoint inhibitors. COTI-2 was deemed generally safe and well-tolerated. Part 2 of the study is currently underway in HNSCC patients, with additional data expected in 2018, and Part 3 will follow with expansion to combination treatment of ovarian and HNSCC patients."

Clinical • IO biomarker • P1 data • Endometrial Cancer • Head and Neck Cancer

Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux. (PubMed, J Med Chem) - "Investigations using Triapine-resistant SW480/Tria and newly established COTI-2-resistant SW480/Coti cells revealed distinct structure-activity relationships. Thus, only thiosemicarbazones forming stable, nonreducible copper(II)-glutathione adducts are recognized and, in turn, effluxed by ABCC1. This reveals a crucial connection between copper complex chemistry, glutathione interaction, and the resistance profile of clinically relevant thiosemicarbazones."

Clinical • Journal • Oncology