Abstract 660: OPN-6602, a potent dual EP300/CBP bromodomain inhibitor, targets multiple myeloma through concomitant suppression of IRF4 and c-MYC
Authors: Matusow Bernice , Spevak Wayne , Zhang Chao , Ma Yan , Shellooe Rafe , Tsai James , Li Pei Pei , Yu Chen Pan , Habets Gaston , Nichols Christine , Singh Parmveer , Inokuchi Kerry , Walling Jackie , Halladay Jason , Bollag Gideon 
Published: March 2024

Abstract
Multiple myeloma (MM) is an aggressive hematological cancer derived from malignant plasma cells in the bone marrow. E1A-binding protein (EP300) and CREB-binding protein (CBP) are transcription coactivators that contain both epigenetic writer histone acetyltransferase (HAT) and reader bromo- (BRD) domains that regulate transcription of genes via chromatin remodeling. EP300/CBP inhibition causes cell cycle arrest and apoptosis in MM through suppression of interferon regulatory factor (IRF4) and concomitant repression of c-MYC, rendering EP300/CBP as a novel target for MM. OPN-6602 is a potent, selective, and orally active small molecule dual EP300/CBP inhibitor discovered through structure guided drug design. Its binding interaction exhibits low nM activity on EP300 (Kd= 1.5 nM) and CREBBP (Kd= 1 nM), with &gt; 200-fold less activity against BRD4. OPN-6602 binding to EP300 is particularly potent by Surface Plasmon Resonance analysis, displaying a Kd of 0.87 nM, with a fast association rate (1.5 E+06/Ms) and a slow dissociation rate (1.3 E-03/s) with a residence time of 13 min. It potently inhibits cell growth in MM cell lines OPM-2 (IC50 ~ 4 nM) and MM.1S (IC50 ~ 47 nM) as well as histone acetylation (IC50 ~ 2 nM) via BRD intramolecular modulation of HAT activity. OPN-6602 demonstrated potent inhibition of H3K27Ac in both LK2 (CBP-deficient lung cancer cells, IC50 = 11 nM) and in OPM-2 (IC50 = 1.6 nM). OPN-6602 also potently inhibited H3K27ac expression in PBMCs with IC50s of 0.75 and 1.4 nM, respectively. The effects of OPN-6602 with dexamethasone (dex) or lenalidomide (len) on the growth of OPM-2 and MM1.S cells were evaluated in a matrix combination study. As single agents, maximal growth inhibition reached 60-75% following dex treatment and only 30-40% following len treatment. In vitro combination studies utilizing a systematic assessment of a broad range of OPN-6602 concentrations in combination with dex or len demonstrated strong synergy. Synergy was observed between OPN-6602 at 3.7 nM and len through a concentration range from 0.027 to 20 µM. Synergy was observed with 1.2 or 3.7 nM of OPN-6602 in combo with dex concentrations from 0.055 to 40 µM. In the OPM-2 xenograft model, OPN-6602 inhibits tumor growth by 30-111% at doses from 2.5-60 mg/kg QD. This growth inhibition correlated with downregulation of IRF4 and cMYC in tumor samples analyzed by QPCR analysis. The pharmacokinetic profile is favorable for oral QD dose administration due to a high Cmax (19 µg/mL at 24 mg/kg) and short half-life (T1/2 = 1.5 hr). A first-in-human study of OPN-6602 in patients with MM is planned for 2024.
Citation Format: Bernice Matusow, Wayne Spevak, Chao Zhang, Yan Ma, Rafe Shellooe, James Tsai, Pei Pei Li, Pan Yu Chen, Gaston Habets, Christine Nichols, Parmveer Singh, Kerry Inokuchi, Jackie Walling, Jason Halladay, Gideon Bollag. OPN-6602, a potent dual EP300/CBP bromodomain inhibitor, targets multiple myeloma through concomitant suppression of IRF4 and c-MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 660.