Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA.
Cell Chem Biol. 2024 Feb 15;31(2):326-337.e11. doi: 10.1016/j.chembiol.2023.10.023. Epub 2023 Nov 27.
PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.
PIM 激酶在肿瘤发生中具有重要的促进作用，并介导多种致癌特征，包括细胞增殖、存活和化疗耐药性。因此，多种 PIM 抑制剂已被作为癌症的研究性新药进行研究；然而，实体瘤对 PIM 抑制剂的反应却低于预期。我们发现，抑制 PIM 激酶活性可以稳定三种 PIM 同工型（PIM1/2/3）的蛋白水平，这可能会导致对 PIM 抑制剂和化疗的耐药性。为了克服这种影响，我们设计了 PIM 蛋白水解靶向嵌合体（PROTACs）来靶向 PIM 进行降解。PIM PROTACs 通过泛素蛋白酶体途径有效地降低了 PIM 水平。重要的是，与抑制其催化活性相比，降解 PIM 激酶在诱导前列腺癌细胞系模型细胞凋亡方面更为有效。总之，我们提供了证据，证明降解 PIM 激酶优于抑制其催化活性，以靶向 PIM 激酶的致癌功能。
