JH-RE-06

A novel inhibitor of mutagenic translesion synthesis (TLS), disrupting mutagenic TLS by preventing recruitment of mutagenic POL ζ, targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ, inducing REV1 dimerization to block the REV1-REV7 interaction.

What is JH-RE-06?

• JH-RE-06 is a small-molecule inhibitor of REV1 (a key translesion DNA synthesis, TLS, polymerase). PMC+3PubMed

• It is designed to disrupt mutagenic TLS by interfering with the protein–protein interactions necessary for recruiting the error-prone polymerase POL ζ (via the REV1–REV7 interaction).

Mechanism of Action

1. Blocking REV1–REV7 / POL ζ recruitment

   • JH-RE-06 is reported to bind to the C-terminal domain (CTD) of REV1 at (or near) the interface with REV7. Cell+5PubMed

   • Binding of JH-RE-06 induces dimerization of REV1 (i.e. two REV1 monomers form a dimer) in a conformation that sterically precludes REV7 (and thereby POL ζ) from binding. PMC+4PubMed

   • Because POL ζ is not recruited, the mutagenic TLS pathway (error-prone bypass of DNA lesions) is suppressed. PMC+4PMC+4PubMed+4

2. Sensitization to DNA damage / chemotherapy

   • By inhibiting the mutagenic TLS pathway, JH-RE-06 increases the sensitivity of cells to DNA damaging agents (e.g. cisplatin) because they can less efficiently bypass DNA damage via error-prone polymerases. PMC+4PubMed+4PMC+4

   • In co-treatment experiments, JH-RE-06 + cisplatin reduced tumor growth more than cisplatin alone in xenograft models. aps.anl.gov+4PMC+4PubMed+4

3. Modulating cellular response (senescence, DNA damage signaling, etc.)

   • Rather than strictly increasing apoptosis, some studies found that combining JH-RE-06 with cisplatin pushes cells toward senescence-like phenotypes (e.g. upregulation of p21, SA-β-galactosidase staining) and persistent DNA damage. PubMed+1

   • In colon / colorectal cancer cells more recently, JH-RE-06 has been reported to induce ferroptosis (an iron-dependent, lipid peroxidation–driven cell death mode), via NCOA4-mediated ferritinophagy (i.e. degradation of ferritin to increase free iron). This suggests an additional or alternative cell death mechanism in certain contexts. Spandidos Publications

4. Tumor suppression in various models / cancer types

   • In melanoma xenografts, JH-RE-06 + cisplatin led to better survival than either alone. aps.anl.gov+2PMC+2

   • In lung cancer, REV1 has been implicated as having oncogenic roles; JH-RE-06 was shown to suppress proliferation, and its effect was dependent on REV1 expression (i.e. in REV1 knockdown, the compound loses efficacy). Nature

   • Safety data in mouse models suggest that JH-RE-06 did not produce overt organ toxicity (based on histology or body weight) in studied regimens. Nature+1

Strengths, Limitations & Considerations

Strengths / promising features:

• It targets a difficult protein–protein interface (REV1–REV7) — historically “undruggable” surfaces. Spandidos Publications+4PubMed+4ScienceDirect+4

• As a TLS inhibitor, it offers dual advantages: sensitization to DNA damage (so less effective bypass) and reduction of mutagenesis (i.e. fewer therapy-induced mutations / resistance). PMC+3Frontiers+3ScienceDirect+3

• The ability to push cancer cells into senescence or alternate death modes (e.g. ferroptosis) gives multiple possible “routes” to reduce cell viability. Spandidos Publications+2PubMed+2

• In vivo tumor suppression and apparently tolerable safety in preclinical models make it a credible lead for further development. Nature+2PMC+2

Limitations & challenges:

• Because JH-RE-06 modifies a relatively subtle PPI rather than an active enzymatic pocket, potency and specificity are always concerns. The effective concentration required may be relatively high.

• The impact is context dependent: in cell lines or tumor types with low reliance on mutagenic TLS, efficacy may be limited.

• Inducing senescence rather than apoptosis may not fully eliminate tumor cells — senescent cells might have pro-tumorigenic secretory phenotypes or could escape.

• For ferroptosis induction, the context (e.g. colorectal cancer) may influence whether that pathway is engaged or not.

• Translational challenges remain: pharmacokinetics, off-target binding, long-term toxicity, tumor heterogeneity, delivery to tumor cells, etc.

• As of now, I did not find evidence of clinical trials publicly for JH-RE-06 (i.e. it is still a preclinical / research tool).

0°C (short term), -20°C (long term), desiccated

1) REV1-POLς Inhibition Enhances Cisplatin-Induced Cytotoxicity. Cancer Discov. 2019 Jun 14.

2) Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P. A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy. Cell. 2019 Jun 4.