OTX-015

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.

OTX-015 以浓度依赖性方式抑制 BRD2、BRD3 和 BRD4 与乙酰化组蛋白 4 的结合，IC₅₀ 值为 92-112nM ^[1].

OTX-015 在九个 AML 细胞系中的六个和所有四个 ALL 细胞系中测量到显着的生长抑制:HEL IC₅₀ 值为 248 nM，NB4 IC₅₀值为 233 nM，NOMO-1 IC₅₀ 值为 229 nM，KG1 IC₅₀ 值为 198 nM，OCI-AML3 IC₅₀ 值为Kasumi IC₅₀ 值为 60 nM，Kasumi IC₅₀ 值为 17 nM，JURKAT IC₅₀ 值为 249 nM，BV-173 IC₅₀ 值为 161 nM , TOM-1 IC₅₀ 值为 133 nM, RS4-11 IC₅₀ 值为 34 nM^[2]。如临床药代动力学评估所述，在胶质母细胞瘤细胞系中体外使用 OTX-015 获得的 GI50 值与在血液系统恶性肿瘤患者中正在进行的 Ib 期临床研究中以无毒剂量治疗的患者血浆中获得的值相同。 OTX-015 在胶质母细胞瘤细胞系组中显示出更高的效力 (GI50 618.1 nM)。 OTX-015 在淋巴瘤和神经母细胞瘤细胞中发挥抗增殖作用并延缓肿瘤生长，同时下调 C-MYC、MYCN 和与超增强子相关的基因^[3]。

OTX-015，在原位人胶质母细胞瘤模型中提供显着的体内生存优势，并在所有给药方案的异位模型中减缓肿瘤进展。此外，在任何 OTX-015 给药方案中都没有发现毒性，这与使用替莫唑胺治疗导致明显的体重减轻形成鲜明对比。 OTX-015 与目前用于治疗 GBM 患者的几种抗肿瘤药物的协同和相加活性，在没有毒性的情况下同时结合 OTX-015 和替莫唑胺提高小鼠存活率，支持将 OTX-015 作为表观遗传调节剂纳入与替莫唑胺联合治疗胶质母细胞瘤^[3]。