4HF Biotec GmbH, Freiburg, Germany.
Charles River, Discovery Research Services GmbH, Freiburg, Germany.
Cancer Res Commun. 2023 Oct 25;3(10):2170-2181. doi: 10.1158/2767-9764.CRC-22-0221.
BI-847325 is an ATP-competitive inhibitor of MEK/Aurora kinases with the potential to treat a wide range of cancers. In a panel of 294 human tumor cell lines in vitro, BI-847325 was found to be a highly selective inhibitor that was active in the submicromolar range. The most sensitive cancer types were acute lymphocytic and myelocytic leukemia, melanomas, bladder, colorectal, and mammary cancers. BI-847325 showed a broader range of activity than the MEK inhibitor GDC-0623. The high efficacy of BI-847325 was associated with but not limited to cell lines with oncogenic mutations in NRAS, BRAF, and MAP2K1.The high antiproliferative activity of BI-847325 was validated in vivo using subcutaneous xenograft models. After oral administration of 80 and 40 mg/kg once weekly for 3 or 4 weeks, BI-847325 was highly active in four of five colorectal, two of two gastric, two of two mammary, and one of one pancreatic cancer models (test/control < 25%), and tumor regressions were observed in five of 11 cancer models. The treatment was well tolerated with no relevant lethality or body weight changes. In combination with capecitabine, BI-847325 displayed synergism over single-agent therapies, leading to complete remission in the triple-negative mammary model MAXFTN 401, partial regression in the colon model CXF 1103, and stasis in the gastric models GXA 3011 and GXA 3023. In conclusion, dual MEK/Aurora kinase inhibition shows remarkable potential for treating multiple types of hematologic and solid tumors. The combination with capecitabine was synergistic in colorectal, gastric, and mammary cancer.
We report the preclinical evaluation of BI-847325, a MEK/Aurora kinase inhibitor. Our data demonstrate that BI-847325 has potent antitumor activity in a broad range of human solid and hematologic cancer models in vitro and in vivo and is well tolerated in animal models. It also shows synergistic effect when combined with capecitabine. These findings provide a strong rationale for further development of BI-847325 as a potential therapeutic for patients with cancer.
BI-847325 是一种 ATP 竞争性的 MEK/极光激酶抑制剂，具有治疗多种癌症的潜力。在体外的 294 个人类肿瘤细胞系中，BI-847325 被发现是一种高度选择性的抑制剂，在亚微摩尔范围内具有活性。最敏感的癌症类型是急性淋巴细胞和髓细胞白血病、黑色素瘤、膀胱癌、结直肠癌和乳腺癌。BI-847325 的活性范围比 MEK 抑制剂 GDC-0623 更广。BI-847325 的高效性与其相关，但不限于 NRAS、BRAF 和 MAP2K1 致癌突变的细胞系。BI-847325 的高抗增殖活性在体内使用皮下异种移植模型得到了验证。每周口服 80 和 40mg/kg 一次，连续 3 或 4 周后，BI-847325 在五个结直肠癌、两个胃癌、两个乳腺癌和一个胰腺癌模型中的四个（测试/对照<25%）中高度活跃，并且在 11 个癌症模型中的五个中观察到肿瘤消退。治疗耐受性良好，无相关致死率或体重变化。与卡培他滨联合使用时，BI-847325 与单一药物治疗相比具有协同作用，导致三阴性乳腺癌模型 MAXFTN 401 完全缓解，结肠癌模型 CXF 1103 部分缓解，胃癌模型 GXA 3011 和 GXA 3023 稳定。总之，双重 MEK/极光激酶抑制显示出治疗多种血液系统和实体肿瘤的巨大潜力。与卡培他滨联合使用在结直肠癌、胃癌和乳腺癌中具有协同作用。
我们报告了 BI-847325（一种 MEK/极光激酶抑制剂）的临床前评估。我们的数据表明，BI-847325 在体外和体内广泛的人类实体瘤和血液系统肿瘤模型中具有强大的抗肿瘤活性，并且在动物模型中耐受性良好。它与卡培他滨联合使用时也具有协同作用。这些发现为进一步开发 BI-847325 作为癌症患者的潜在治疗方法提供了强有力的理论依据。
