Authors' Affiliations: Oncology Disease Area Research; Global Discovery Chemistry/Oncology and Exploratory Chemistry; MAP Group; Chemical and Pharmaceutical Profiling Group, Novartis Institutes for Biomedical Research, Emeryville, California; Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; Oncology Disease Area Research; and Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Clin Cancer Res. 2014 Apr 1;20(7):1834-45. doi: 10.1158/1078-0432.CCR-13-2062. Epub 2014 Jan 28.
PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies.
Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low Km for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context.
LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model.
We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies.
已经证明 PIM 激酶在小鼠中作为癌基因发挥作用，每个家族成员都能够推动血液癌症的进展。与此一致，我们发现 PIM 在人类血液癌症中高度表达，并表明每种同工型在疾病亚型中具有独特的表达模式。这表明所有三种 PIM 的抑制剂都将在治疗多种血液恶性肿瘤方面有效。
泛 PIM 抑制剂的开发一直很困难，因为 PIM2 对 ATP 的 Km 较低，因此需要非常有效的抑制剂才能在细胞的 ATP 水平有效阻断激酶活性。我们开发了一种有效的、特异性的泛 PIM 抑制剂 LGB321，它在细胞环境中对 PIM2 有效。
LGB321 对依赖 PIM2 的多发性骨髓瘤细胞系有效，在这些细胞系中，它抑制增殖、mTOR-C1 信号传导和 BAD 的磷酸化。LGB321 对广泛的癌细胞系进行的特征分析表明，它在源自实体瘤的细胞系中活性有限。相比之下，在源自不同血液谱系的细胞系中观察到显著的活性，包括急性淋巴细胞白血病 (ALL)、急性髓细胞性白血病 (AML)、多发性骨髓瘤和非霍奇金淋巴瘤 (NHL)。此外，我们在 KG-1 AML 异种移植模型中证明了 LGB321 的活性，其中药效动力学标志物的调节可预测疗效。最后，我们证明 LGB321 在该模型中与阿糖胞苷协同作用。
我们开发了一种有效的、选择性的泛 PIM 抑制剂，具有单一药物的增殖抑制活性，并表明它在 AML 异种移植模型中与阿糖胞苷协同作用。我们的结果强烈支持开发泛 PIM 抑制剂来治疗血液恶性肿瘤。
