Small Molecule Inhibitors of CRL4 Ubiquitin Ligase for Cancer Treatment

Background & Unmet Need

• Cullin 4 (CUL4) is a molecular scaffold of the CUL4-RING ubiquitin ligase (CRL4), which controls the stability and cellular levels of proteins via the ubiquitin-proteasome pathway
• CUL4 proteins play a significant role in  nucleotide excision repair after UV irradiation, as well as the cell cycle, cell signaling, and histone methylation
• CUL4A is amplified or expressed at abnormally high levels in multiple cancers, including breast cancer, squamous cell carcinoma, hepatocellular carcinomas, and lung cancer
• Moreover, CUL4A and 4B overexpression is implicated in tumor progression, metastasis, and a poorer survival rate for patients with lung, colorectal, cervical, esophageal, and breast cancers
• Unmet Need: Novel inhibitors of CUL4 proteins for treatment of CUL4-expressing cancers

Technology Overview

• The Technology: Specific inhibitors of CUL4 for treatment of CUL4-expressing cancers
• The Discovery: CUL4 inhibitors were identified through a robust high-throughput screening and assay workflow of ~240K compounds
• Lead compounds were subsequently optimized via several rounds of SAR to produce the current lead compounds PA-201 and PA-1
• Compounds are currently in the hit-to-lead stage, with additional medicinal chemistry to improve potency ongoing
• PoC Data: PA-1 demonstrates tumor killing ability in vitro and in in vivo xenograft models of MDA-MB-468 breast cancer cells, a CUL4-high cell line
• shRNA CUL4 inhibition sensitizes tumors to the topoisomerase 1 inhibitor topotecan (P=9.1E-3), suggesting that CUL4 inhibitors may be combined with chemotherapy

Technology Applications

• Precision cancer therapy for patients with CUL4-high tumors, such as CUL4-high colorectal, breast, lung, and ovarian cancer

Technology Advantages

• CUL4 is overexpressed and linked to tumor progression and metastasis in multiple tumor types, providing for multi-indication development 
• CUL4 is a readily measurable biomarker, enabling precision medicine strategies

Figure 1: Graphical abstract of CUL4 ubiquitin ligase system