PO.MCB03.02 · 分子与细胞生物学
利用一种FDA批准药物抑制HUNK作为HER2+乳腺癌潜在治疗策略的生化与细胞学评估
Biochemical and cellular evaluation of HUNK inhibition by an FDA approved drug as potential therapeutic strategy for HER2+ breast cancer
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摘要 Abstract
中文摘要
自Imatinib获批以来，激酶抑制剂一直是抗癌药物研发的焦点，近期FDA批准了第100个小分子激酶抑制剂，展示了激酶抑制剂在肿瘤治疗及其他领域的潜力。HER2激酶是乳腺癌治疗中公认的药物靶点，随着时间推移已开发出多种针对该靶点的抑制剂。然而，肿瘤对这些抑制剂逐渐产生耐药性仍是侵袭性乳腺癌治疗中的一个预后难题。近期研究乳腺癌HER2耐药机制发现，HUNK（激素上调的neu相关激酶）通过磷酸化Rubicon在促进HER2+乳腺癌细胞存活及抑制剂耐药中发挥关键作用。近期已鉴定并表征出首个同类HUNK靶向抑制剂HSL119，证实靶向HUNK作为HER2耐药乳腺癌治疗策略的潜力，但针对该靶点仍有待鉴定出更强效的抑制剂。为此，我们在Reaction Biology的HotSpot检测平台上通过HUNK生化激酶检测筛选了145种FDA批准的化合物，鉴定出Momelotinib——一种口服的JAK1/JAK2/ACVR1抑制剂，用于治疗骨髓纤维化——以7.9 nM的IC50抑制HUNK。NanoBRET靶点结合检测证实Momelotinib在活的HEK293细胞中结合细胞内HUNK。此外，CellTiter-Glo检测表明Momelotinib抑制HER2+ JIMT1细胞和三阴性4T1乳腺癌细胞的增殖，而caspase-3/7激活检测表明Momelotinib在两种细胞系中均诱导凋亡性细胞死亡。这些发现凸显Momelotinib作为克服乳腺癌HER2抑制剂耐药的潜在治疗候选药物。
查看英文原文 English abstract
Kinase inhibitors have been on spotlight for cancer drug discovery ever since the approval of Imatinib and recently the 100 th small molecule kinase inhibitor was approved by the FDA showing the potential of kinase inhibitors for cancer therapeutics and beyond. HER2 kinase is an established drug target in breast cancer therapeutics with multiple inhibitors developed against this target over time. However, cancer developing drug resistance to these inhibitors over time remain as a prognostic challenge for aggressive breast cancer treatment. Recent studies investigating the HER2 resistance mechanism of breast cancers identify HUNK (hormonally upregulated neu-associated Kinase) playing a crucial role in promoting HER2+ breast cancer cell survival and inhibitors resistance via phosphorylation of Rubicon. Recently a first in class HUNK targeted inhibitor HSL119 has been identified and characterized to demonstrate potential of targeting HUNK as a treatment strategy for HER2 resistant breast cancers, but more potent inhibitors for this target are yet to be identified. To address this, we screened 145 FDA approved compounds in HUNK biochemical kinase assay in Reaction Biology's HotSpot assay platform and identified Momelotinib, an orally available JAK1/JAK2/ACVR1 inhibitor used to treat myelofibrosis, inhibiting HUNK with 7.9 nM IC 50 . NanoBRET target engagement assay confirmed Momelotinib binds cellular HUNK in live HEK293 cells. Furthermore, CellTiter-Glo assays demonstrated Momelotinib inhibits proliferation of HER2+ JIMT1 cells and triple-negative 4T1 breast cancer cells, while caspase-3/7 activation assays indicated Momelotinib induces apoptotic cell death in both lines. These findings highlight Momelotinib as a potential therapeutic candidate for overcoming HER2 inhibitor resistance in breast cancer.
利益披露 Disclosure
S. F. AbdulSalam, None.