Abstract 3991: Novel small molecule inhibitors of p300/CBP down-regulate androgen receptor (AR) and c-Myc for the treatment of prostate cancer and beyond

Abstract

Abstract Background: E1A binding protein (p300) and CREB binding protein (CBP), two paralogue histone acetyl transferase proteins, act as transcriptional co-activators of a variety of cancer related genes. We have developed CCS1477, a potent, selective and orally active small molecule inhibitor of the bromodomain of p300/CBP and investigated its role in regulating AR and c-Myc expression and function, for the treatment of prostate cancer and haematological malignancies. We have also examined the role of p300/CBP in driving synthetic lethality in tumours with loss of function mutations (eg. bladder cancer). Methods: Potency and functional activity was evaluated in a panel of prostate cells lines representing hormone responsive, hormone independent and castration resistant disease. Effects of CCS1477 on AR, AR-V7 splice variant and c-Myc protein, as well as KLK3, c-Myc, UBE2C, CCNA2 and TMPRSS2 gene expression, were assessed. Inhibition of proliferation and function by CCS1477 was also examined in acute myeloid leukaemia cell lines and patient derived primary AML cells. In addition, potency was determined in bladder cell lines possessing a loss of function mutation in p300/CBP and compared to wild type. Results: CCS1477 is a potent inhibitor of cell proliferation in castration resistant prostate cell lines (IC50 = 96nM 22Rv1; 49nM VCaP) with minimal effect in AR-ve lines (PC3 and DU145). Treatment of 22Rv1 and VCaP cells with CCS1477 significantly reduced expression of KLK3, UBE2C and CCNA2 in the presence and absence of enzalutamide indicating compromised signalling via AR and AR-SV. Furthermore, AR and AR-SV protein levels were inhibited in response to CCS1477 treatment. Utilising an enzalutamide-resistant cell line (LNCaP-ARF876L), CCS1477 treatment down-regulated both androgen and enzalutamide-stimulated KLK3 and TMPRSS2 gene expression. CCS1477 dosed at 20mg/kg qd caused complete tumour growth inhibition in a 22Rv1 xenograft model. CCS1477 is also a potent inhibitor of proliferation in AML cell lines (IC50 ~ 100nM; THP-1; MV4-11), with effects mediated by G1 cell cycle arrest and accompanied by myeloid differentiation. Comparable results are observed on patient derived primary AML cells. In bladder cancer cell lines, we observed differential sensitivity to CCS1477 with p300/CBP deficient lines (IC50 = 300nM VM-CUB-2 and 647V) compared with wild type (no activity at 30uM, RT112). Conclusions: Taken together these data support the clinical testing of p300/CBP inhibition in patients in three settings; (i) castration resistant prostate cancer through down-regulating AR, AR-SV and c-Myc expression and function; (ii) haematological cancers by effects on cell cycle arrest and myeloid differentiation, and (iii) patients with loss of function mutations in p300 or CBP by driving synthetic lethality. Citation Format: Neil Pegg, Jenny Worthington, Barbara Young, Amy Prosser, Luke Gaughan, Gary Spencer, Tim Somervaille, Julie Burns, Margaret Knowles, Nigel Brooks. Novel small molecule inhibitors of p300/CBP down-regulate androgen receptor (AR) and c-Myc for the treatment of prostate cancer and beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3991.