Monotherapy HPV E7 Oncoprotein

RDP has identified a first-in-class, orally available, small molecule-based new chemical entity (NCE) which induces the proteolysis of the human papilloma virus (HPV)-associated E7 oncoprotein. Our lead compound VS035 was selected from more than 64 million compounds that were screened using computer cavity docking simulations (in silico screens). Following selection, 1,000 molecules were chemically synthesized and tested using a proprietary E7 assay. Single agent efficacy of VS035 and OC246 (our back-up compound) has been demonstrated in an HPV-dependent cervical cancer xenograft model. Both compounds reveal clear single agent inhibition of E7 activity. Additionally, and highly promising no toxicity has been observed to date in mice. VS035 degrades E7, thereby preventing tumour-induced cell signalling and uncontrolled cell division.  Moreover, treatment results in, reactivation of the adaptive (as well as the innate) immune response.

It is anticipated that cervical, vulvar, and anal intraepithelial neoplasia could be treated with VS035 monotherapy. Patients suffering from invasive disease might benefit from combination therapies of composed of VS035 and PD1/PDL1 inhibitors leading to a potential cure for HPV-induced cancer.

Specifications for inhibitor selection:

  • Clear activity in HPV-induced xenograft model
  • Oral availability and favorable pharmacokinetics
  • Ability to decompose E7 within its in vivo half-life
  • Low toxicity
  • Compliance with the “Lipinski rule of 5” (drug-ability)
  • Ease of synthesis and favourable upscaling properties
  • Strong patentability (new composition of matter patent and beyond)
PDF is available for download here and here.