BACKGROUND & AIMS:
:p38α mitogen-activated protein kinase (MAPK) is activated in cancer cells in response to environmental factors, oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production of cytokines in the tumor microenvironment, such as TNF-α, interleukin-1β (IL-1β), IL-6, and CXCL8 (IL-8). p38α MAPK is highly expressed in human cancers and may play a role in tumor growth, invasion, metastasis, and drug resistance. LY2228820 dimesylate (hereafter LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and β-isoforms of p38 MAPK in vitro (IC(50) = 5.3 and 3.2 nmol/L, respectively). In cell-based assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC(50) = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 μmol/L. LY2228820 also reduced TNF-α secretion by lipopolysaccharide/IFN-γ-stimulated macrophages (IC(50) = 6.3 nmol/L). In mice transplanted with B16-F10 melanoma, tumor phospho-MK2 (p-MK2) was inhibited by LY2228820 in a dose-dependent manner [threshold effective dose (TED)(70) = 11.2 mg/kg]. Significant target inhibition (>40% reduction in p-MK2) was maintained for 4 to 8 hours following a single 10 mg/kg oral dose. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer.
背景与目标:
:p38α丝裂原激活蛋白激酶(MAPK)在癌细胞中被激活,以响应环境因素,致癌性应激,放射和化学疗法。 p38αMAPK磷酸化许多底物,包括MAPKAP-K2(MK2),并调节肿瘤微环境中细胞因子的产生,例如TNF-α,白介素-1β(IL-1β),IL-6和CXCL8(IL -8)。 p38αMAPK在人类癌症中高表达,并可能在肿瘤生长,侵袭,转移和耐药性中发挥作用。 LY2228820二甲磺酸酯(以下称LY2228820)是三取代的咪唑衍生物,是体外有效的p38 MAPKα和β亚型的ATP竞争性抑制剂(IC(50)分别为5.3和3.2 nmol / L) 。在基于细胞的分析中,LY2228820有效地和选择性地抑制了由茴香霉素刺激的HeLa细胞(蛋白印迹分析为9.8 nmol / L)和由茴香霉素诱导的小鼠RAW264.7巨噬细胞(IC(50)= 35.3)中MK2(Thr334)的磷酸化(nmol / L),但p38αMAPK,JNK,ERK1 / 2,c-Jun,ATF2或c-Myc≤10μmol/ L的磷酸化没有变化。 LY2228820还通过脂多糖/IFN-γ刺激的巨噬细胞(IC(50)= 6.3 nmol / L)减少了TNF-α的分泌。在移植有B16-F10黑色素瘤的小鼠中,LY2228820以剂量依赖性方式抑制肿瘤磷酸化MK2(p-MK2)[阈值有效剂量(TED)(70)= 11.2 mg / kg]。单次口服10 mg / kg剂量后,显着抑制靶标(p-MK2降低40%以上)。 LY2228820在多种体内癌症模型(黑色素瘤,非小细胞肺癌,卵巢癌,神经胶质瘤,骨髓瘤,乳腺癌)中产生了显着的肿瘤生长延迟。总之,LY2228820是一种p38 MAPK抑制剂,已针对人类癌症动物模型的效价,选择性,类药物特性(例如口服生物利用度)和功效进行了优化。