Abstract 1348: Targeted degradation of PARP14 Using a heterobifunctional small molecule

T. Wigle, Yue Ren, J. Molina, Daniel J. Blackwell, L. Schenkel, K. Swinger, Anne Cheug, R. Abo, E. Minissale, A. Lu, C. Majer, W. Church, B. W. Dorsey, M. Niepel, N. R. Perl, K. Kuplast-Barr, K. McEachern, M. Vasbinder, H. Keilhack, K. Kuntz
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Abstract

PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types and has been shown to promote the pro-tumor M2 polarization of macrophages and support Th2/Th17 signaling in models of allergic airway disease. PARP14 is a large 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrates, three macrodomains that bind mono-ADP-ribose, a WWE domain that serves as a binding module for poly-ADP-ribose, and an RNA recognition motif. We have previously shown that the potent and reversible enzymatic inhibitor, RBN012759 (IC50 1,000-fold selective over polyPARPs), links PARP14 catalytic inhibition with suppression of the antitumor immune response in human primary macrophages and human kidney cancer explants. While this catalytic inhibitor of PARP14 was able to suppress IL-4-driven pro-tumor gene expression in macrophages, it is unknown what roles the non-enzymatic biomolecular recognition motifs play in the biological function of PARP14. To further understand this, we describe a heterobifunctional small molecule, RBN012811, based on a catalytic inhibitor of PARP14 that binds in the enzyme9s NAD+-binding site and recruits the E3 ligase cereblon to ubiquitinate PARP14 and selectively target it for degradation. RBN012811 has a IC50 of 0.01 μM against PARP14 in a biophysical assay and is at least 200-fold selective over all other PARPs. In KYSE-270 cancer cells, RBN012811 has a half-maximal degradation concentration (DC50) of 0.005 μM and it does not cause degradation of other PARP enzymes. In human primary macrophages PARP14 degradation by RBN012811 led to a dose-dependent decrease of IL-10 release induced by IL-4 stimulation. Our data demonstrates that RBN012811 is a useful tool to enable further exploration of the role of PARP14 in inflammation and cancer. Citation Format: Tim Wigle, Yue Ren, Jennifer Molina, Danielle Blackwell, Laurie Schenkel, Kerren Swinger, Anne Cheug, Ryan Abo, Elena Minissale, Alvin Lu, Christina Majer, William Church, Bryan Dorsey, Mario Niepel, Nicholas Perl, Kristy Kuplast-Barr, Kristen McEachern, Melissa Vasbinder, Heike Keilhack, Kevin Kuntz. Targeted degradation of PARP14 Using a heterobifunctional small molecule [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1348.
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1348:利用异双功能小分子靶向降解PARP14
PARP14是一种干扰素刺激基因,在多种肿瘤类型中过表达,已被证明在变应性气道疾病模型中促进巨噬细胞的促瘤M2极化和支持Th2/Th17信号传导。PARP14是一个203 kDa的大蛋白,具有一个催化结构域,负责将单adp核糖转移到其底物,三个结合单adp核糖的大结构域,一个作为多adp核糖结合模块的WWE结构域和一个RNA识别基序。我们之前已经证明,有效且可逆的酶抑制剂RBN012759 (IC50比polyPARPs选择性1000倍)将PARP14的催化抑制与人原代巨噬细胞和人肾癌外植体的抗肿瘤免疫反应的抑制联系起来。虽然这种PARP14的催化抑制剂能够抑制巨噬细胞中il -4驱动的促肿瘤基因表达,但目前尚不清楚非酶促生物分子识别基序在PARP14的生物学功能中起什么作用。为了进一步理解这一点,我们描述了一种基于PARP14催化抑制剂的异双功能小分子RBN012811,它结合在酶9nad +结合位点,招募E3连接酶小脑使PARP14泛素化,并选择性地靶向降解PARP14。在生物物理实验中,RBN012811对PARP14的IC50为0.01 μM,比所有其他parp的选择性至少高200倍。在KYSE-270癌细胞中,RBN012811的半最大降解浓度(DC50)为0.005 μM,不引起其他PARP酶的降解。在人原代巨噬细胞中,RBN012811降解PARP14导致IL-4刺激诱导的IL-10释放呈剂量依赖性降低。我们的数据表明,RBN012811是一个有用的工具,可以进一步探索PARP14在炎症和癌症中的作用。引文格式:Tim Wigle, Yue Ren, Jennifer Molina, Danielle Blackwell, Laurie Schenkel, Kerren Swinger, Anne Cheug, Ryan Abo, Elena Minissale, Alvin Lu, Christina Majer, William Church, Bryan Dorsey, Mario Niepel, Nicholas Perl, Kristy kuplust - barr, Kristen McEachern, Melissa Vasbinder, Heike Keilhack, Kevin Kuntz。利用异双功能小分子靶向降解PARP14[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):1348。
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