What is p53?
p53 is a tumor suppressor protein that tightly regulates cell proliferation and cell death and plays a critical role in maintaining genetic stability to prevent the malignant transformation of healthy cells.1-3
Cellular repair or cell death occurs when stress signals activate p53 in response to DNA damage, hypoxia, cytokine release, viral infection, or oncogene signaling. The dysfunction of p53 significantly contributes to the development and progression of cancer.1-3
How Does p53 Work?
p53 response to cellular stress varies by the nature and severity of the activating insult.1-3
Reversible DNA damage induces low levels of p53 expression which activates p21, a key regulator of cell-cycle arrest and DNA repair. Irreparable DNA damage activates higher levels of p53 expression which upregulates pro-apoptotic proteins to induce cell death.1-3
p53 and Cell Death
p53 and Cell Death
The MDM2 Protein
Murine double minute 2 (MDM2) is the critical negative regulator of p53 cellular function, with the fate of a cell determined by a delicate balance between MDM2 and p53 protein levels.6,7
In healthy cells, activated MDM2 maintains p53 at very low levels. In cancer, however, malignant cells resist activated p53 cell killing by mutating p53 or abnormally elevating MDM2 levels, resulting in unchecked cancer cell proliferation.1,2
Navtemadlin is a potent and selective investigational cancer therapy designed to inhibit the MDM2 protein.8
In cell cultures and pre-clinical cancer models, navtemadlin inhibited MDM2 at low drug concentrations and induced dose-dependent activation of p53.9
Cell-cycle arrest through p21 activation and subsequent induction of cell death by pro-apoptotic Bcl-2 family proteins resulted in complete and durable regression of tumors.9
TreatingCancer with Navtemadlin
In early clinical cancer studies, navtemadlin induced cancer cell death by blocking DNA synthesis and increasing the expression of pro-apoptotic Bcl-2 family proteins.10
In patients with blood cancers and solid tumors, navtemadlin treatment inhibited MDM2 and restored p53 function.10,11
Encouraging clinical activity has been reported in patients with advanced cancers, including Myelofibrosis, Acute Myeloid Leukemia, and Merkel cell carcinoma.10,12-14
Additional novel cancer studies are ongoing.
A New Path Forward
Our mission is to improve the lives of cancer patients through a deep understanding of cancer biology, translational sciences, and novel applications of navtemadlin alone and in combination with other cutting-edge cancer therapeutics. Stay tuned for exciting updates and new data presentations in 2023.Active clinical studies
Treating Cancer with Navtemadlin
In early clinical cancer studies, navtemadlin induced cell death by blocking DNA synthesis and increasing the expression of pro-apoptotic Bcl-2 family proteins. In patients with blood cancers and solid tumors, navtemadlin treatment inhibited MDM2 and restored p53 function. Encouraging clinical activity has been reported in patients with advanced cancers, including Myelofibrosis, Acute Myeloid Leukemia, and Merkel cell carcinoma. Additional cancer studies are ongoing and planned for 2023.
A New Path Forward
At Kartos Therapeutics, we aspire to improve the lives of cancer patients, supported by a deep understanding of cancer biology, translational sciences, and novel applications of first-in-class treatments like navtemadlin alone and in combination with other cutting-edge cancer therapeutics.Active clinical studies
Kastenhuber ER and Lowe SW. Putting p53 in context. Cell. 2017; 170: 1062-1078.
Horn HF and Vousden KH. Coping with stress: multiple ways to activate p53. Oncogene. 2007; 26: 1306-1316.
Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000; 408: 307-310.
Aubrey BJ, Kelly GL, Janic A, et al. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018; 25: 104-113.
Vaseva AV and Moll UM. The mitochondrial p53 pathway. Biochim Biophys Acta. 2009; 1787: 414-420.
Bond GL, Hu W, Levine AJ. MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets. 2005; 5: 3-8.
Iwakuma T, Lozano G. MDM2, an introduction. Mol Cancer Res. 2003; 1: 993-1000.
Sun D, Li Z, Rew Y, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014; 57: 1454-1472.
Canon J, Osgood T, Olson SH, et al. The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. Mol Cancer Ther. 2015; 14: 649-658.
Erba HP, Becker PS, Shami PJ, et al. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia. Blood Adv. 2019; 3: 1939-1949.
Gluck WL, Gounder MM, Frank R, et al. Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced p53 wild-type solid tumors or multiple myeloma. Invest New Drugs. 2020; 38: 831-843.
Al-Ali HK, Garcia Delgado R, Lange A, et al. KRT‑232, a first‑in‑class, murine double minute 2 inhibitor (MDM2i), for myelofibrosis (MF) relapsed or refractory (R/R) to Janus‑associated kinase inhibitor (JAKi) treatment (TX). HemaSphere. 2020; 4:65. Abstract S215.
Vachhani P, Lange A, Garcia Delgado R, et al. Potential disease-modifying activity of navtemadlin (KRT-232), a first-in-class MDM2 inhibitor, correlates with clinical benefits in relapsed/refractory myelofibrosis (MF). Blood. 2021; 138 (Supplement 1): 3581.
Wong MKK, Kelly CM, Burgess M, et al. KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53WT) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy. J Clin Oncol. 2020; 38(15_suppl): 10072.