NSC59984 / Penn State Hershey Medical Center - LARVOL DELTA

NSC59984 is a radiosensitizer and cytotoxic agent in in vitro and in vivo models of TP53mut endometrial cancer (AACR 2025) - "NSC59984 has cytotoxic and radiosensitizing effects in in vitro and in vivo models of TP53mut EC. These effects are independent of specific TP53 mutations, suggesting it bypasses inactive p53 to drive p21, PUMA, and NOXA signaling. The synergistic effect is within biologically relevant doses and supports the need for further preclinical investigation in a disease with significant unmet need and poor outcomes."

Preclinical • Endometrial Cancer • Oncology • Solid Tumor • CDKN1A

Moxibustion's Impact on Ferroptosis Regulation: A Key to Relieving Inflammatory Injury in Rheumatoid Arthritis. (PubMed, Rejuvenation Res) - "In the corresponding groups, moxibustion treatment was carried out using cigarette-like moxa strips that were suspended near "Shenshu" (BL23) and "Zusanli" (ST36) once daily for 15 days, and the p53 agonist NSC59984 was administered intraperitoneally...The levels of SLC7A11, GPX4, and GSH were the opposite. Moxibustion can improve RA synovial inflammatory injury by regulating ferroptosis through inhibition of p53 protein expression."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • GPX4 • IL1B • SLC7A11 • TNFA

NSC59984 as a potent radiosensitizer and cytotoxic agent in TP53-mutated endometrial cancer (SGO 2025) - No abstract available

Endometrial Cancer • Oncology • Solid Tumor • TP53

Chlorophyllides repress gain-of-function p53 mutated HNSCC cell proliferation via activation of p73 and repression of p53 aggregation in vitro and in vivo. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "In our previous study, co-treatment with p73 activator NSC59984 and NAMPT inhibitor FK886 synergistically repressed Detroit 562 cell proliferation...Moreover, NAMPT was repressed by chlorophyllides independent of p73 status in vivo. We thus concluded that chlorophyllides have a dual anticancer function when applied to HNSCC cells with p53 gain-of-function mutation, via activation of p73 and repression of p53 aggregation."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP3 • CASP7 • NAMPT • TP53

Covalent Modification of p53 by (E)-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one. (PubMed, ACS Pharmacol Transl Sci) - "Finally, we used a biotinylated form of NSC59984 and, separately, thermal proteome profiling to examine off-target effects, identifying several metabolic proteins involved in cellular metabolism as potential targets. These results demonstrate that covalent modification of p53 by NSC59984 leads to increased wild-type activity and suggest that potential reaction with metabolic enzymes may contribute to antiproliferative function."

Journal • Oncology

Mutant p53 reactivators protect breast cancer cells from ferroptosis. (PubMed, Cell Biochem Funct) - "One of these p53 reactivator molecules, NSC 59984, reduced expression of GPX4, which is unlikely to explain its ability to reduce sensitivity to ferroptosis. We suggest that these p53 reactivators function via an unknown, p53-independent manner to suppress ferroptosis."

Journal • Breast Cancer • Oncology • Solid Tumor • GPX4 • TP53

Small molecule NSC59984 synergizes with PARP inhibitors in BRCA1 wild type ovarian cancer (AACR 2024) - "ABT263, NSC59984 + PARPi combinational treatment further reduced cell viability. Our study provides a rationale for small molecular compounds targeting HR deficiency in combination with PARPi to treat BRCA1wild-type ovarian cancer cells, and additional senolytic treatment may be required to limit resistance by removal of the TIS."

Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA1 • RAD51 • TP53

Small molecule NSC59984 stimulates mitochondria-dependent ferroptosis and overcomes integrated stress response pro-survival signaling in pre-clinical pancreatic and colorectal cancer models (AACR 2024) - "The combination therapy overcomes the ISR to induce potent cell death. Our work demonstrates the importance of the interplay between mitochondria and the ISR during ferroptosis induction in pancreatic and colorectal cancer cells."

Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CDC37 • GPX4 • HSP90AA1 • HSPA5 • SLC7A11

DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation. (PubMed, Cancers (Basel)) - "Cotreatment of THP-1 cells with venetoclax and a TP53 activator NSC59984 downregulated DRP1 expression and increased apoptosis. These findings suggest that DRP1 is functionally associated with venetoclax sensitivity in TP53-mutated AML cells. Targeting DRP1 may represent an effective therapeutic strategy for overcoming venetoclax resistance in TP53-mutated AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • MCL1

Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile. (PubMed, Front Oncol) - "Overall, these findings demonstrate p53-dependent effects of NSC59984 on cellular metabolism, with increased activity in cells harboring the p53 R248W mutation. This research highlights the importance of defining the mutational status of a particular cancer to create a patient-centric strategy for the treatment of p53-driven cancers."

Journal • Colorectal Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • TP53

Contact-dependent signaling triggers tumor-like proliferation of CCM3 knockout endothelial cells in co-culture with wild-type cells. (PubMed, Cell Mol Life Sci) - "The observation that NSC59984, an anticancer drug, blocked the abnormal proliferation of mutant endothelial cells further supports this intriguing concept...These results support the hypothesis that wild-type ECs facilitate the formation of a niche that promotes abnormal proliferation of mutant ECs. Thus, targeting the cancer-like features of CCMs is a promising new direction for drug development."

Journal • Hematological Disorders • Oncology