PNC-27

Key Benefits#

• Selective cytotoxicity against cancer cells overexpressing HDM2/MDM2
• Spares normal cells lacking surface HDM2 expression
• Membranolytic mechanism bypasses intracellular resistance pathways
• Demonstrated activity against breast, pancreatic, leukemia, and melanoma cell lines
• Potential for combination with conventional chemotherapy
• Novel non-genotoxic anticancer mechanism

Mechanism of Action#

PNC-27 carries a p53-derived peptide sequence (residues 12-26) fused to a penetratin leader sequence. In cancer cells, which overexpress HDM2 on the plasma membrane, PNC-27 binds HDM2 and inserts into the lipid bilayer via the penetratin sequence. This causes membrane disruption (membranolysis) and rapid cancer cell death. Normal cells, which do not express surface HDM2, are spared. The mechanism is distinct from intracellular p53 pathway restoration.

Dosing Protocols#

Side Effects#

• Limited human clinical data; largely in vitro and animal studies
• Potential immunogenic reactions (foreign peptide)
• Systemic toxicity at high doses not well characterized
• Unknown interactions with current chemotherapy agents

Contraindications#

No approved human use; investigational compound onlyNot recommended outside clinical trial settingsPregnancy: absolutely contraindicated

Storage#

Lyophilized: store at -20 degrees C. Reconstituted: use within 7 days refrigerated at 2-8 degrees C. Protect from light and avoid freeze-thaw cycles.

1. 1.
   HDM-2-Targeting Peptide PNC-27 Kills Cervical Cancer Cells but not Normal Cervical Cells

   Krzesaj PK, Seydafkan S, Miller AI, Chen HT, Premsrirut P, Shim A et al. · Annals of clinical and laboratory science · 2025PubMed Verified

2. 2.
   Poptosis or Peptide-Induced Transmembrane Pore Formation: A Novel Way to Kill Cancer Cells without Affecting Normal Cells

   Pincus MR, Silberstein M, Zohar N, Sarafraz-Yazdi E, Bowne WB · Biomedicines · 2024ReviewPubMed Verified

3. 3.
   Anti-Cancer Peptide PNC-27 Kills Cancer Cells by Unique Interactions with Plasma Membrane-Bound hdm-2 and with Mitochondrial Membranes Causing Mitochondrial Disruption

   Krzesaj P, Adler V, Feinman RD, Miller A, Silberstein M, Yazdi E et al. · Annals of clinical and laboratory science · 2024PubMed Verified

4. 4.
   Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents

   Miller AI, Diaz D, Lin B, Krzesaj PK, Ustoyev S, Shim A et al. · Biomedicines · 2023PubMed Verified

5. 5.
   The role of ETFS amino acids on the stability and inhibition of p53-MDM2 complex of anticancer p53-derivatives peptides: Density functional theory and molecular docking studies

   Soriano-Correa C, Vichi-Ramírez MM, Herrera-Valencia EE, Barrientos-Salcedo C · Journal of molecular graphics & modelling · 2023PubMed Verified

6. 6.
   Conjugated PNC-27 peptide/PEI-superparamagnetic iron oxide nanoparticles (SPIONs) as a double targeting agent for early cancer diagnosis: In vitro study

   Rahmani R, Darroudi M, Gharanfoli M, Chamani J, Gholamin M, Hashemi M · Iranian journal of basic medical sciences · 2022PubMed Verified

7. 7.
   PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis

   Sarafraz-Yazdi E, Mumin S, Cheung D, Fridman D, Lin B, Wong L et al. · Biomedicines · 2022PubMed Verified

8. 8.
   Molecular Targeting of H/MDM-2 Oncoprotein in Human Colon Cancer Cells and Stem-like Colonic Epithelial-derived Progenitor Cells

   Thadi A, Morano WF, Khalili M, Babcock BD, Shaikh MF, Foster DS et al. · Anticancer research · 2021PubMed Verified

9. 9.
   Anti-Cancer Tumor Cell Necrosis of Epithelial Ovarian Cancer Cell Lines Depends on High Expression of HDM-2 Protein in Their Membranes

   Thadi A, Gleeson EM, Khalili M, Shaikh MF, Goldstein E, Morano WF et al. · Annals of clinical and laboratory science · 2020PubMed Verified

10. 10.
    Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells

    Thadi A, Lewis L, Goldstein E, Aggarwal A, Khalili M, Steele L et al. · Anticancer research · 2020PubMed Verified

11. 11.
    Targeting cell membrane HDM2: A novel therapeutic approach for acute myeloid leukemia

    Wang H, Zhao D, Nguyen LX, Wu H, Li L, Dong D et al. · Leukemia · 2020PubMed Verified

12. 12.
    Death of preceding child and maternal healthcare services utilisation in Nigeria: investigation using lagged logit models

    Akinyemi JO, Bolajoko I, Gbadebo BM · Journal of health, population, and nutrition · 2018PubMed Verified

13. 13.
    Synergy between Paclitaxel and Anti-Cancer Peptide PNC-27 in the Treatment of Ovarian Cancer

    Alagkiozidis I, Gorelick C, Shah T, Chen YA, Gupta V, Stefanov D et al. · Annals of clinical and laboratory science · 2017PubMed Verified

14. 14.
    Ex vivo Efficacy of Anti-Cancer Drug PNC-27 in the Treatment of Patient-Derived Epithelial Ovarian Cancer

    Sarafraz-Yazdi E, Gorelick C, Wagreich AR, Salame G, Angert M, Gartman CH et al. · Annals of clinical and laboratory science · 2015PubMed Verified

15. 15.
    P53-Derived peptides conjugation to PEI: an approach to producing versatile and highly efficient targeted gene delivery carriers into cancer cells

    Mokhtarzadeh A, Parhiz H, Hashemi M, Abnous K, Ramezani M · Expert opinion on drug delivery · 2016PubMed Verified

16. 16.
    The anti-cancer peptide, PNC-27, induces tumor cell necrosis of a poorly differentiated non-solid tissue human leukemia cell line that depends on expression of HDM-2 in the plasma membrane of these cells

    Davitt K, Babcock BD, Fenelus M, Poon CK, Sarkar A, Trivigno V et al. · Annals of clinical and laboratory science · 2014PubMed Verified

17. 17.
    Design and implementation of a high yield production system for recombinant expression of peptides

    Rodríguez V, Asenjo JA, Andrews BA · Microbial cell factories · 2014PubMed Verified

18. 18.
    Anti-cancer peptides from ras-p21 and p53 proteins

    Pincus MR, Fenelus M, Sarafraz-Yazdi E, Adler V, Bowne W, Michl J · Current pharmaceutical design · 2011ReviewPubMed Verified

19. 19.
    Chondroitin sulfate as a molecular portal that preferentially mediates the apoptotic killing of tumor cells by penetratin-directed mitochondria-disrupting peptides

    Yang H, Liu S, Cai H, Wan L, Li S, Li Y et al. · The Journal of biological chemistry · 2010PubMed Verified

20. 20.
    The anti-cancer peptide, PNC-27, induces tumor cell lysis as the intact peptide

    Sookraj KA, Bowne WB, Adler V, Sarafraz-Yazdi E, Michl J, Pincus MR · Cancer chemotherapy and pharmacology · 2010PubMed Verified

21. 21.
    Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

    Sarafraz-Yazdi E, Bowne WB, Adler V, Sookraj KA, Wu V, Shteyler V et al. · Proceedings of the National Academy of Sciences of the United States of America · 2010PubMed Verified

22. 22.
    The penetratin sequence in the anticancer PNC-28 peptide causes tumor cell necrosis rather than apoptosis of human pancreatic cancer cells

    Bowne WB, Sookraj KA, Vishnevetsky M, Adler V, Sarafraz-Yazdi E, Lou S et al. · Annals of surgical oncology · 2008PubMed Verified

23. 23.
    Electronic structure and physicochemical properties characterization of the amino acids 12-26 of TP53: a theoretical study

    Barrientos-Salcedo C, Arenas-Aranda D, Salamanca-Gómez F, Ortiz-Muñiz R, Soriano-Correa C · The journal of physical chemistry. A · 2007PubMed Verified

24. 24.
    A case-crossover analysis of out-of-hospital coronary deaths and air pollution in Rome, Italy

    Forastiere F, Stafoggia M, Picciotto S, Bellander T, D'Ippoliti D, Lanki T et al. · American journal of respiratory and critical care medicine · 2005PubMed Verified

25. 25.
    NMR solution structure of a peptide from the mdm-2 binding domain of the p53 protein that is selectively cytotoxic to cancer cells

    Rosal R, Pincus MR, Brandt-Rauf PW, Fine RL, Michl J, Wang H · Biochemistry · 2004PubMed Verified