First-in-class IKK-alpha Selective Inhibitors for Cancer Treatment

Scientists in Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS) are developing first-in-class selective inhibitors targeting IKK alpha (“IKKα”) non-canonical NF-κB driven pathway to combat aggressive inflammatory-driven cancers and diseases. Pre-clinical studies for inflammation-driven colorectal cancer(“CRC”) and prostate cancer (“PC”) including castrate-resistant (“CRPC”) are ongoing.

Background

Chronic inflammation is a driving factor in the pathogenesis of CRPC and CRC, promoting immune suppression, metastasis, and resistance to treatment. By regulating multiple cytokine pathways and promoting tumour proliferation, IKKα contributes to a hostile, treatment-resistant microenvironment. Preclinical and clinical evidence supports IKKα as a target for therapy.

Existing IKK inhibitor strategies, which include small molecules, gene therapy and RNA-based therapy have mainly been directed towards IKKβ leading to undesired side effects and limited therapeutic efficacy. To our knowledge, we are the only team to have developed a lead compound series against IKKα with significant selectivity over IKKβ.

Our inhibitors show anti-tumour responses in-vitro and in-vivo, setting the programme to be the most advanced IKK-targeted oncology therapies in the public academic research and commercial market landscape.

Stage of Development

Our preclinical lead optimisation programme, supported by MRC-DPFS funding (£2.59M), is focused on improving pharmacokinetic properties towards a preclinical candidate.

Benefits

  • 100-fold selectivity over IKKβ across numerous cell lines
  • current lead compound SU1644 has demonstrated strong anti-cancer activity in multiple PC cell lines (IC50 range of 0.23-0.37µM) 
  • potent dose-dependent anti-tumour responses in patient-derived prostate cancer explants 
  • response to our current lead compound significantly outperforms the current standard-of-care agent enzalutamide (Xtandi) in potency and consistency of response in all models
  • slowed growth of PC xenografts in mice
  • therapeutic value in attenuating osteolysis-associated advanced secondary PC in metastatic bone murine models
  • efficacy in multiple patient-derived CRC organoid models

Applications

In addition to colorectal cancer and prostate cancer, the compounds are demonstrating utility in other inflammatory-driven cancers and disease.

Intellectual property

Two composition of matter patents have been filed (2022 and 2023) and are in national/regional phase and PCT respectively.