NOT FOR HUMAN CONSUMPTION

PNC-27 is a 27-mer chimeric peptide in which the p53 HDM-2–binding motif (residues 12-26) is covalently fused to a penetratin-derived “membrane-residency peptide” (MRP) that drives lipid-bilayer insertion. The construct, together with the close analogue PNC-28, was first disclosed in the international patent WO2009070650A1 and assigned to the SUNY Downstate inventors (sub-licensing now held by Oncolyze, Inc.).

2 Molecular Mechanism — From Target Recognition to “Poptosis”

Result: PNC-27 lyses tumour cells in minutes while sparing normal cells that lack surface HDM-2.

3 Pre-clinical Efficacy Dossier

4 Selectivity and Toxicology

• Maximum tolerated dose (mouse): 2 mg day⁻¹ IP for 28 d with no weight loss, behavioural changes or gross-organ toxicity.

• Normal-cell window: Fibroblasts, endothelial cells, PBMCs and marrow progenitors withstand ≥10× tumour-lytic concentrations.

• Open questions: No GLP repeat-dose, reproductive or large-animal studies; immunogenicity is uncharacterised; systemic inflammatory sequelae of extensive tumour necrosis have not been modelled.

5 Pharmaceutical and Manufacturing Issues

6 Regulatory and Legal Landscape

• FDA status: No INDs or authorised clinical trials; 2017 FDA alert classifies PNC-27 as an unapproved drug and highlights contamination risks.

• Criminal enforcement: U.S. v. Patrick Bishop (2021) – guilty plea for manufacturing and interstate sale of misbranded PNC-27 products made in a domestic kitchen/warehouse.j

• Marketing abuses: Multiple websites still purport “overseas clinical success” but provide no registry numbers or peer-reviewed data.

7 Critical Knowledge Gaps Blocking Translation

1. Human pharmacokinetics and metabolism are wholly undefined.

2. Immunogenicity of repeated dosing and risk of neutralising antibodies remain unknown.

3. HDM-2 expression plasticity under stress (infection, hypoxia, chemotherapy) may narrow the therapeutic window in vivo.

4. Resistance evolution – long-term exposure might select HDM-2-negative tumour clones; no studies yet.

5. Companion diagnostics to stratify patients by membrane HDM-2 expression are lacking.

8 Roadmap to First-in-Human Development

1. GMP manufacture with validated identity, purity, sterility and endotoxin profiles to resolve past quality failures.

2. GLP toxicology in rodents and a non-rodent (e.g., canine) model, including repeat-dose and safety-pharmacology endpoints.

3. Phase I trial design: dose-escalation in refractory solid tumours or AML with confirmed high membrane HDM-2; intensive PK and cytokine monitoring.

4. Imaging or IHC biomarker for membrane HDM-2 to guide enrolment and pharmacodynamics.

5. Combination cohorts with paclitaxel or platinum agents to validate pre-clinical synergy.

9 Balanced Assessment

PNC-27 delivers a mechanistically elegant, membrane-targeted oncolytic strategy that bypasses p53 status and chemosensitivity. Laboratory evidence demonstrates rapid, selective destruction of a wide spectrum of cancer cells, including chemo-resistant populations, with a large in-vitro therapeutic index. Conversely, the peptide has no human pharmacology, no GLP toxicology, and a documented history of contaminated grey-market products and regulatory enforcement. Until rigorous manufacturing and clinical studies are completed, PNC-27 remains an intriguing but unvalidated research lead rather than a viable therapeutic.

References

1. Yefet L et al. PNC-27, a chimeric p53-penetratin peptide binds to HDM-2, induces selective membrane-pore formation and cancer-cell lysis. Biomedicines 2022;10:945.

2. Annunziata CM et al. Synergy between paclitaxel and anti-cancer peptide PNC-27 in the treatment of ovarian cancer. Ann Clin Lab Sci 2017;47:271-9.

3. U.S. FDA. FDA warns cancer patients not to use PNC-27 products for treatment. Safety Communication, 10 Jan 2017 (updated 27 Mar 2017).

4. U.S. Department of Justice. Birmingham man pleads guilty to conspiracy for making unapproved drug products in his kitchen and warehouse. Press release, 21 Jan 2021.

5. Hall DJ et al. Small-molecule cancer treatments that cause pore formation leading to necrosis of cancer cells.WO2009070650A1 (international patent).

6. Li X et al. Targeting cell-membrane HDM2: a novel therapeutic approach for acute myeloid leukaemia. Cell Death Dis 2021;12:298.

7. Sarraf G et al. PNC-27 adopts an HDM-2-binding conformation and induces selective membranolysis of cancer cells. Proc Natl Acad Sci USA 2009;106:20352-7.