Wigle Tim J, Ren Yue, Molina Jennifer R, Blackwell Danielle J, Schenkel Laurie B, Swinger Kerren K, Kuplast-Barr Kristy, Majer Christina R, Church W David, Lu Alvin Z, Mo Jason, Abo Ryan, Cheung Anne, Dorsey Bryan W, Niepel Mario, Perl Nicholas R, Vasbinder Melissa M, Keilhack Heike, Kuntz Kevin W
Ribon Therapeutics, 35 Cambridgepark Dr., Suite 300, Cambridge, MA 02140, USA.
Chembiochem. 2021 Jun 15;22(12):2107-2110. doi: 10.1002/cbic.202100047. Epub 2021 May 4.
PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types, influencing pro-tumor macrophage polarization as well as suppressing the antitumor inflammation response by modulating IFN-γ and IL-4 signaling. PARP14 is a 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrates. PARP14 also contains three macrodomains and a WWE domain which are binding modules for mono-ADP-ribose and poly-ADP-ribose, respectively, in addition to two RNA recognition motifs. Catalytic inhibitors of PARP14 have been shown to reverse IL-4 driven pro-tumor gene expression in macrophages, however it is not clear what roles the non-enzymatic biomolecular recognition motifs play in PARP14-driven immunology and inflammation. To further understand this, we have discovered a heterobifunctional small molecule designed based on a catalytic inhibitor of PARP14 that binds in the enzyme's NAD -binding site and recruits cereblon to ubiquitinate it and selectively target it for degradation.
PARP14是一种干扰素刺激基因，在多种肿瘤类型中过表达，通过调节IFN-γ和IL-4信号传导影响促肿瘤巨噬细胞极化并抑制抗肿瘤炎症反应。PARP14是一种203 kDa的蛋白质，具有负责将单ADP-核糖转移至其底物的催化结构域。PARP14还包含三个大结构域和一个WWE结构域，分别是单ADP-核糖和多ADP-核糖的结合模块，此外还有两个RNA识别基序。PARP14的催化抑制剂已被证明可逆转IL-4驱动的巨噬细胞中促肿瘤基因表达，然而尚不清楚非酶促生物分子识别基序在PARP14驱动的免疫和炎症中发挥何种作用。为进一步了解这一点，我们发现了一种基于PARP14催化抑制剂设计的异双功能小分子，它结合在该酶的NAD结合位点，并招募cereblon使其泛素化并选择性地靶向降解。
