OTX-015 (Synonyms: HY15743, (-)-OTX015)

OTX-015 inhibits the binding of BRD2, BRD3, and BRD4 to acetylated histone 4 in a concentration-dependent manner, with IC₅₀ values from 92-112nM ^[1].

OTX-015 significant growth inhibition was mesured in six of nine AML cell lines and all four ALL cell lines: HEL IC₅₀ value as 248 nM, NB4 IC₅₀ value as 233 nM, NOMO-1 IC₅₀ value as 229 nM, KG1 IC₅₀ value as 198 nM, OCI-AML3 IC₅₀ value as 60 nM, Kasumi IC₅₀ value as 17 nM, JURKAT IC₅₀ value as 249 nM, BV-173 IC₅₀ value as 161 nM, TOM-1 IC₅₀ value as 133 nM, RS4-11 IC₅₀ value as 34 nM^[2]. GI50 values obtained with OTX-015 in vitro in glioblastoma cell lines were equivalent to those achieved in plasma from patients treated at nontoxic doses in the ongoing Phase Ib clinical study in patients with hematologic malignancies, as described in a clinical pharmacokinetics evaluation. OTX-015 displayed higher potency (GI50 618.1 nM) in glioblastoma cell line panel. OTX-015 exerted antiproliferative effects and delayed tumor growth in lymphoma and neuroblastoma cells, together with a downregulation of C-MYC, MYCN and genes associated with superenhancers^[3].

OTX-015, offering a significant survival advantage in vivo in the orthotopic human glioblastoma model and slowing tumor progression in the heterotopic model with all administration regimens. Furthermore, no toxicity was seen with any of the OTX-015 dosing regimens, in direct contrast to treatment with temozolomide which induced pronounced weight loss. Synergistic and additive activity of OTX-015 in combination with several antitumor agents currently used to manage GBM patients, improving mouse survival with simultaneous combination of OTX-015 and temozolomide in the absence of toxicity, supporting the incorporation of OTX-015 as an epigenetic modulator in combination with temozolomide in glioblastoma ^[3].

References:
[1]. J. Kay Noel, et al. Abstract C244: Development of the BET bromodomain inhibitor OTX015. Mol Cancer Ther November 2013 12; C244.
[2]. Marie-Magdelaine Coudé, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015 Jul 10; 6(19): 17698–17712.
[3]. Berenguer-Daize C, et al. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016;139(9):2047–2055.