CP-31398 / Pfizer - LARVOL DELTA

p53 enhances elesclomol-Cu-induced cuproptosis in hepatocellular carcinoma via FDXR-mediated FDX1 upregulation. (PubMed, Front Oncol) - "p53 overexpression/knockdown, siRNA-mediated ferredoxin reductase (FDXR)/FDX1 knockdown, and the p53 activators CP-31398 and nutlin-3 were employed to elucidate the associated molecular mechanisms. These findings revealed that p53 enhances elesclomol-Cu-induced cuproptosis in HCC via FDXR-mediated FDX1 upregulation. This study provides mechanistic insights into p53's role in cuproptosis and may serve as a basis for targeting copper metabolism in therapeutic strategies for HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • DLAT • FDX1 • FDXR

Repurposing of apoptotic inducer drugs against Mycobacterium tuberculosis. (PubMed, Sci Rep) - "The in-vitro MIC assay showed that cepharanthine (CEP) had the highest antimycobacterial activity against Mycobacterium smegmatis mc2155 and Mycobacterium tuberculosis H37Rv, with MICs of 3.1 and 1.5 µg/mL, respectively, followed by CP-31398 dihydrochloride hydrate (DIH) (MICs = 6.2 and 3.1 µg/mL, respectively), marinopyrrole A (MAR) (MICs = 25 and 12.5 µg/mL, respectively), and nutlin-3a (NUT) (MICs = 50 and 25 µg/mL, respectively)...This study highlights the importance of probing already existing chemical scaffolds as a starting point for discovery of therapeutic agents against M. tuberculosis H37Rv using both pathogen and host directed approaches. The integration of molecular dynamics simulations provides valuable insights into potential scaffold modifications to enhance the affinity."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • IL1B • TNFA

Styrylquinazoline derivatives as ABL inhibitors selective for different DFG orientations. (PubMed, J Enzyme Inhib Med Chem) - "Our previous studies have shown interesting kinases inhibition activity for a series of 4-aminostyrylquinazolines based on the CP-31398 scaffold...Finally, in-depth cellular studies revealed the full landscape of the mechanism of action of the most active compounds. We conclude that S-substituted styrylquinazolines can be considered as a promising scaffold for the development of multi-kinase inhibitors targeting a desired binding mode to kinases as effective anticancer drugs."

Journal • Hematological Malignancies • Leukemia • Oncology

Reactivation of p53 by RITA Induces Apoptosis in Human Oral Squamous Cell Carcinoma Cells. (PubMed, Anticancer Res) - "The inhibitory effect of RITA on human OSCC cell proliferation is mediated by apoptosis induction through p53 and Bax."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5 • BAX • CA9 • MDM2

Comparative activation of cellular ISR and cell death induction by p53 pathway restoring small molecules (AACR 2022) - "To perform a comparative activation of p53 target genes, novel compounds PG3 and PG3-Oc that activate a subset of p53-target genes in a p53-independent manner, and four known mutant p53-activating compounds were included (ZMC1, APR-246, CP-31398 and Ellipticine). Nutlin-3a was used as a negative control...We identified PUMA-mediated cell apoptosis through activation of caspase-8 in HT29 cells and possibly caspase-10 in SW480 cells. In summary, we provide a new mechanism that PG3 induced cell death via an HRI/ATF4/PUMA axis that may be helpful in understanding drug efficacy."

Oncology • ATF4 • CASP10 • CASP8 • CDKN1A • GDF15

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

Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest. (PubMed, Cancers (Basel)) - "Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398...Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents."

Journal • Brain Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Glioblastoma • Hematological Malignancies • Hepatology • Leukemia • Oncology • Pancreatic Cancer • Solid Tumor • CDK1

The pharmalogical reactivation of p53 function improves breast tumor cell lysis by granzyme B and NK cells through induction of autophagy. (PubMed, Cell Death Dis) - "This CP31398-induced autophagy sequestrates in autophagosomes several anti-apoptotic proteins, including Bcl-X and XIAP, facilitating Granzyme B-mediated mitochondrial outer membrane permeabilization, caspase-3 activation and Granzyme B- or NK cell-induced apoptosis. Together, our results define a new way to increase cytotoxic lymphocyte-mediated lysis of p53-mutated breast cancer cell, through a p53-dependent autophagy induction, with potential applications in combined immunotherapeutic approaches."

IO Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor

A Slug-dependent mechanism is responsible for tumor suppression of p53-stabilizing compound CP-31398 in p53-mutated endometrial carcinoma. (PubMed, J Cell Physiol) - "Finally, the in vivo experimental evidence confirmed that CP-31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP-31398-regulated Slug downregulation represses the p53-mutated EC via the p53/Wnt/Puma pathway."

IO Biomarker • Journal • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2

High-throughput screening yields several small-molecule inhibitors of repeat-associated non-AUG translation. (PubMed, J Biol Chem) - "Using circular dichroism and native gel analyses, we found evidence that three of these compounds, BIX01294, CP-31398, and propidium iodide, bind directly to the repeat RNAs. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • Ataxia • CNS Disorders • Complement-mediated Rare Disorders • Dementia • Frontotemporal Lobar Degeneration • Movement Disorders

Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype. (PubMed, Apoptosis) - "In contrasts, nutlin-3a, an MDM2 inhibitor, increased p53 and p21 levels in mesothelioma with the wild-type p53 genotype and produced growth suppressive effects. Combination of CP-31398 and defactinib, a FAK inhibitor, also achieved synergistic inhibitory effects and increased p53 with FAK dephosphorylation levels greater than the single treatment. These data indicated that a p53-activating CP-31398 achieved growth inhibitory effects in combination with a MDM2 or a FAK inhibitor and suggested a possible reciprocal pathway between p53 elevation and FAK inactivation."

Journal • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • Thoracic Cancer • CASP3 • CDKN2A • PARP • PARP1

p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. (PubMed) - "The present study showed that p53 is required for metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. The combination of metformin with p53 reactivating agents, like nutlin-3α and CP/31398, is a promising strategy for improving metformin-mediated anti-cancer therapy, especially for tumors with p53 mutations."

Journal • Biosimilar • Breast Cancer • Oncology • Triple Negative Breast Cancer

p53 modulates Hsp90 ATPase activity and regulates aryl hydrocarbon receptor signaling. (PubMed) - "Treatment with CP-31398, a p53 rescue compound, suppressed benzo[a]pyrene-mediated induction of CYP1A1 and CYP1B1 and the formation of DNA adducts. Collectively, our results suggest that p53 affects AhR-dependent gene expression, PAH metabolism, and possibly carcinogenesis."

Journal • Biosimilar • Oncology

Potential synergistic effects of sorafenib and CP-31398 for treating anaplastic thyroid cancer with p53 mutations. (PubMed, Oncol Lett) - "The decreased viability of SW579 cells, following CP-31398 treatment, was augmented by sorafenib, and CP-31398 enhanced the antimitogenic effect of sorafenib; thus, sorafenib and CP-31398 synergistically inhibited the growth of SW579 cells. These results indicate a potential clinical application of CP-31398 for patients with ATC harboring p53 abnormalities, since these individuals generally respond poorly to sorafenib alone."

Journal

2-Styryl-4-aminoquinazoline derivatives as potent DNA-cleavage, p53-activation and in vivo effective anticancer agents. (PubMed, Eur J Med Chem) - "Forty-eight analogues of CP-31398, an antitumor agent modulated the mutant p53 gene were synthesized and their cytotoxicities against four cancer cell lines with different p-53 status including bladder cell T24 (w-p53), gastric cell MGC-803 (m-p53), prostate cell DU145 (m-p53), prostate cell PC-3 (null-p53), lung cell A549 (w-p53) and normal liver cell line HL-7702 (w-p53) were examined...10ah-treatment in MGC-803 cells increased the expression of p53, phosphorylated p53 (p-p53), CDK4, p21 to cause cell cycle arrest at G2/M phase, significantly up-regulated the levels of pro-apoptosis proteins Bak, Bax, Bim while down-regulated the anti-apoptosis proteins Bcl-2, Bcl-xL and the levels of cyclin B1, fluctuated the intracellular reactive oxygen species (ROS), Ca and mitochondrial membrane potential, activated Caspase-9 and Caspase-3 to induce apoptosis. 10ah also displayed potent anticancer efficiency against MGC-803 xenograft tumors models, with tumor growth inhibition..."

IO Biomarker • Journal • Preclinical

CP-31398 inhibits the progression of cervical cancer through reversing the epithelial mesenchymal transition via the downregulation of PAX2s. (PubMed, J Cell Physiol) - "Moreover, the tumor formation experiment in nude mice revealed the inhibitory activity of CP-31398 in CC tumor in nude mice by suppressing PAX2. Our results provide evidence that CP-31398 could inhibit EMT and promote apoptosis of CC cells to curb CC tumor growth by downregulating PAX2."

Journal

Co-targeting p53-R249S and CDK4 synergistically suppresses survival of hepatocellular carcinoma cells. (PubMed, Cancer Biol Ther) - "Indeed, co-treatment of p53-RS-containing, but not wild-type p53 or p53-null, HCC cells with PD-0332991 (PD), a CDK4/6 inhibitor, and CP-31398 (CP), a compound that can restore the intrinsic conformation and transcriptional activity of mutant p53, drastically repressed the c-Myc activation function of p53-RS. This combination of PD with CP exhibited a synergistic effect on the inhibition of HCC cell growth in a p53-RS dependent manner, especially at a lower dose. These results suggest that co-targeting CDK4 and p53-RS can serve as a potential approach for the development of an effective therapy for HCC that harbor p53-RS."

Journal • CCND1 • CDK4 • MYC

CP‑31398 attenuates endometrial cancer cell invasion, metastasis and resistance to apoptosis by downregulating MDM2 expression. (PubMed, Int J Oncol) - "Taken together, the findings of this study indicate that the CP‑31398‑mediated downregulation of MDM2 may suppress EC progression via its inhibitory role in EC cell migration, invasion and resistance to apoptosis. Therefore, treatment with CP‑31398 may prove to be possible therapeutic strategy for EC."

Journal

Pharmacological modulation of inflammation and p53 signaling synergize to prevents muscle invasive bladder cancer in-vivo (AACR 2019) - "...Here we investigated a combinatorial approach to modulate inflammation with NSAIDs (licofelone or NO-Naproxen) and p53 signaling pathways using CP-31398 (CP) for preventing MIBC bladder in-vivo...Specifically, NSAID plus CP may be a promising combination for preventing MIBC. (Supported in part by NCI-PREVENT program - NCI-CN-53300)"

Preclinical

The p53 stabilizing agent CP-31398 and multi-kinase inhibitors. Designing, synthesizing and screening of styrylquinazoline series. (PubMed, Eur J Med Chem) - "Their inhibitory activity in a panel of tyrosine kinases had an antiproliferative effect against several cancer cell lines that have different expression levels of those proteins. The mode of protein interaction was tested for the most active compound in docking experiments."

Journal

A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway. (PubMed, Am J Cancer Res) - "Cisplatin, a DNA damaging agent, induced cleavages of PARP and caspase-3 without increase of p53 levels, indicating that the p53 down-stream pathway was disrupted in these cells. We also showed that CP-31398-induced cell cycle changes including increase of G2/M populations was attributable to the up-regulated p21. These data collectively indicated that CP-31398 augmented endogenous p21 levels and induced cell cycle changes through regulation of YY1, and that YY1 was a novel target of CP-31398 in p53 dysfunctional cells."

Journal • PARP Biomarker