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First-in-class inhibitors of Atypical Protein Kinase C (aPKC)
• Opportunity for a first-in-class oncology asset, through parallel preclinical disease positioning and toxicology/phase I plan approach
• Potential to move quickly into clinical areas where there is an unmet need for novel therapeutics: RAS-driven cancers and Hedgehog-driven cancers
• Pre-clinical candidate and advanced back-up molecule with differentiated chemotypes declared
Opportunity for a first-in-class oncology asset, through parallel preclinical disease positioning and toxicology/phase I plan approach.
A collaborative discovery programme between the Cancer Research UK Therapeutic Discovery Laboratories and Teva Pharmaceuticals declared pre-clinical and back-up candidates, prior to Teva shifting strategic focus away from oncology R&D. Both candidate molecules show excellent developability profiles (Table 1 - see overleaf).
Cancer Research UK is pursuing two avenues for disease positioning, both areas of high unmet need: RAS- and HH/GLI1-driven cancers. The aPKC inhibitors restore polarized morphogenesis in dysplastic RAS spheroids , and decrease BCC cell viability in line with GLI1 modulation in vitro (Figure 1 and Table 2), showing potential for PK-PD modelling [6,7]. The pre-clinical candidate displays in vivo efficacy in a PDAC mouse xenograft model derived from pancreatic cancer cells with GLI1 dependency for survival and KRAS-mediated transformation (Figure 2). Significant in vivo efficacy has been demonstrated as single agent in additional tumour xenograft models. Oral administration is well-tolerated, with no significant body weight loss or mortality observed in these dosing regimens, and dose-related plasma/tumour exposure. Interestingly, aPKC inhibitors display an additive effect in combination with the FDA-approved HDAC inhibitor vorinostat against patient-derived BCC explants ex vivo 
aPKCs (PKCι and PKCζ) are AGC protein kinases involved in the establishment and maintenance of cell polarity, and play a role in the initiation and development of oncogene-driven epithelial cancers, including RAS and ERBB2 oncogenes [1-3]. PKCι has also been shown to activate the transcription factor GLI1, downstream of Smoothened (SMO), modulating Hedgehog (HH) activity, a signalling pathway commonly upregulated in basal cell carcinoma (BCC) and pancreatic ductal adenocarcinoma (PDAC), among others [4,5]. Suppression of PKCι activity with the myristoylated aPKC peptide inhibitor PSI prevents BCC progression in SMO inhibitor sensitive and resistant cell lines, and decreases GLI1 transcription factor mRNA levels and tumour size in allografted BCC tumours . As such, there is a clear rationale for targeting aPKC in the context of RAS- and HH/GLI1- driven malignancies.
1. Biochem Pharmacol, 2014. 88(1): 1-11
2. Carcinogenesis, 2014. 35(2): 396-406
3. Dev Cell. 2017. 42(4): 400-415
4. Nature, 2013. 494(7438): 484-8
5. Ther Adv Med Oncol. 2010. 2(4): 237–250
6. JCI Insight, 2017. 2(21): e97071
7. Roffey et al., AACR-NCI-EORTC (2017)
8. Genes Dev. 2009. 23(1): 24-36