Guardian of the Genome

What is p53 and how does it serve the cell in a normal situation?

Known as the guardian of the genome, p53 (Tumor Protein 53) is a tumor suppressor protein that is activated by many forms of cell stress, such as damage to the DNA, oncogene activation, telomere erosion, ribonucleotide depletion, oxidative stress/hypoxia.1,2,3,5,6

The coordinated response of p53 protects cells from malignant transformation and tumor development.8,9

Snipe Science Guardian DN Adamage Kartos Thera

DNA Damage

Snipe Science Guardian Oncogene Kartos Thera

Oncogene Activation

Snipe Science Guardian Telomere Kartos Thera

Telomere Erosion

Snipe Science Guardian Ribo Deplete Kartos Thera

Ribonucleotide Depletion

Snipe Science Guardian Oxidative Kartos Thera

Oxidative Stress/Hypoxia

p53 is activated by cellular stress or genomic damage

Surveillance

p53 protects cells from malignant transformation

Cellular Protection

p53 responses preserve genomic stability

Genetic Stability

Cell Cycle Arrest/Cellular Apoptosis
How does p53 work?

When activated, p53 binds to DNA and initiates gene transcription that leads to production of proteins that stop cell division until DNA can be repaired.7,9,10 If the DNA damage is beyond repair, p53 initiates controlled cell death (apoptosis).9,10,11

In a normal cell, the processes of cell division and cell cycle arrest are very tightly regulated, mediated in part by another protein called MDM2.

What is MDM2 and how does it affect p53?

Mouse double minute 2 homolog, or MDM2, is an enzyme that regulates p53, by keeping p53 levels and activity in check in normal, unstressed cells.12

The MDM2-p53 interaction represents a compelling therapeutic target in cancer.
Mdm2 normal cells kartos

How does MDM2 regulate p53?

MDM2 directly binds to the transactivation domain of p53 which prevents p53 from initiating gene expression. MDM2 tags p53 for proteasomal degradation while also promoting its export from the nucleus to the cytoplasm.1,12,13

Mdm2 cancer cells kartos

What happens to p53 when MDM2 is overexpressed?

Overexpression or amplification of MDM2 in malignant cells limits p53 tumor suppressor functions, allowing uncontrolled cell division in response to aberrant signaling.14,15,16

KRT-232 Mechanism of Action

KRT-232 is an investigational oral small molecule designed as a potent and selective inhibitor of the MDM2-p53 interaction.16,17 By fitting precisely into the p53-interaction domain of MDM2, KRT-232 inhibits MDM2 by preventing it from binding to p53.17

MDM2 inhibition permits p53 to be activated and exert its tumor suppressor functions.14,17,18 Activated p53 halts cell proliferation and can lead to apoptosis in malignant cells. In non-malignant cells, cell cycle arrest allows for DNA repair to occur, which helps prevent new malignancies.

Preclinical data support the further investigation of KRT-232 for its potential therapeutic utility for treating certain types of cancers where MDM2 is overly active.15,16,17,18,19

KRT-232 Trio
KRT-232 Mechanism of Action
Kartos is charting a course for KRT-232 to become a potential new breakthrough therapy.
Active Clinical Studies

References

  1. Horn HF and Vousden KH. Coping with stress: multiple ways to activate p53. Oncogene. 2007; 26: 1306-1316.

  2. Meek DW. Regulation of the p53 response and its relationship to cancer. Biochem. J. 2015; 469, 325–346.

  3. Roake CM, Artandi SE. Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres. Cold Spring Harb Perspect Med. 2017 May 1;7(5).

  4. Linke SP, Clarkin KC, Di Leonardo A, et al. A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev. 1996;10(8):934–47.

  5. Budanov AV. The role of tumor suppressor p53 in the antioxidant defense and metabolism. Subcell Biochem. 2014;85:337-58.

  6. Chowdhury AR, Long A, Fuchs SY, et al. Mitochondrial stress-induced p53 attenuates HIF-1α activity by physical association and enhanced ubiquitination. Oncogene. 2017 Jan 19;36(3):397-409.

  7. Chen Y, Dey R, Chen L. Crystal structure of the p53 core domain bound to a full consensus site as a self-assembled tetramer. Structure. 2010; 18(2), 246–256.

  8. Kaiser AM, Attardi LD. Deconstructing networks of p53-mediated tumor suppression in vivo. Cell Death Differ. 2018 Jan;25(1):93-103.

  9. Williams AB, Schumacher B. p53 in the DNA-Damage-Repair Process. Cold Spring Harb Perspect Med. 2016 May 2;6(5).

  10. Eischen CM. Genome Stability Requires p53. Cold Spring Harb Perspect Med. 2016 Jun 1;6(6).

  11. 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 Jan;25(1):104-113.

  12. Bond GL, Hu W, Levine AJ. MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets. 2005 Feb;5(1):3-8.

  13. Iwakuma T, Lozano G. MDM2, an introduction. Mol Cancer Res. 2003 Dec;1(14):993-1000.

  14. Wade M, Li Y, Wahl GM. (2013). MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nature Reviews Cancer, 13(2), 83-96.

  15. Oliner JD, Saiki AY, Caenepeel S. The Role of MDM2 Amplification and Overexpression in Tumorigenesis. Cold Spring Harb Perspect Med. 2016 Jun 1;6(6) pii: a026336.

  16. Tisato V, Voltan R, Gonelli A, et al. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol. 2017 Jul 3;10(1):133.

  17. 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 Feb 27;57(4):1454-72.

  18. 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 Mar;14(3):649-58.

  19. Kato S, Ross JS, Gay L, Dayyani F, Roszik J, Subbiah V, Kurzrock R. Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies. JCO Precis Oncol. 2018;2018. doi: 10.1200/PO.17.00235. Epub 2018 Jul 13