OPN-6602, an Orally Bioavailable EP300/CBP Bromodomain Inhibitor, Targets Multiple Myeloma through Suppression of IRF4 and MYC
OPN-6602 is a potent, selective, and orally active small molecule dual CBP/EP300 BRD inhibitor. OPN-6602 demonstrates potent antitumor activity in preclinical studies. OPN-6602 inhibits the binding of acetylated histone peptides to the BRDs of EP300 (IC50 = 27 nM) and CBP (IC50 = 31 nM), with greater than 200-fold selectivity versus BET BRDs (IC50 >8000 nM). The potent inhibition of both EP300 and CBP and selectivity against other BRDs thus underlie the pharmacological effects of OPN-6602.
In a screen of 91 cancer cell lines, OPN-6602 is most active in hematopoietic and lymphoid tumors (GI50 <250 nM). Several MM cell lines including OPM-2, U266, and RPMI 8226 were highly sensitive to OPN-6602 with GI50s ~7-21 nM.
OPM-2 is an MM cell line that is dependent on the expression of EP300/CBP. The efficacy of OPN-6602 in combination with dexamethasone (dex) and/or with pomalidomide (pom) or mezigdomide (mezi) was evaluated in the OPM-2 xenograft model. OPN-6602 at 24 mg/kg QD suppressed tumor growth (71% TGI). Addition of dex significantly increased anti-tumor activity (100% TGI) with 3/6 animals exhibiting tumor regressions. For OPN-6602 triplets with dex + pom or dex + mezi, all animals (n=6) exhibited tumor regressions. Dosing for all groups was discontinued after Day 13 to monitor the duration of response. The triplets OPN-6602 + dex + pom and OPN-6602 + dex + mezi exhibited sustained duration of responses of 30 and >42 days, respectively. In a pharmacodynamic study after 3 days of consecutive dosing in the OPM-2 model, RNASeq analysis demonstrates distinct profiles among OPN-6602, dex, pom, and mezi. Indeed, further downregulation of MYC and IRF4 was observed exclusively with the OPN-6602 triplets compared to OPN-6602 single agent or in combination with dex. Interestingly, when OPN-6602 is excluded from the treatment regimen (i.e dex and pom/mezi), the downregulation of MYC and IRF4 is significantly compromised.
The efficacy of OPN-6602 in combination with dex and/or mezi was further evaluated in the MM1.S xenograft model in SCID mice. Synergistic responses were observed with OPN-6602 at 24 mg/kg as a triplet combining dex + mezi with 5/6 animals exhibiting tumor regressions compared to the doublet dex + mezi combo with 1/6 animals exhibiting tumor regressions.
Preclinical safety of OPN-6602 was evaluated in a 28-day GLP toxicology study in CD-1 mice at doses of 0, 15, 50 and 150 mg/kg/day. The no observed adverse effect level (NOAEL) and the severely toxic dose in 10% of animals (STD10) were 15 and 50 mg/kg/day, respectively. There were no significant changes in white blood cell or platelet counts. Similar findings were observed in a dog GLP toxicology study.
OPN-6602 is currently being evaluated in patients with MM in the Phase I clinical trial OPN6602-C01 (NCT06433947).