title: PI3Kβ inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways.
abstract: We aimed to exploit novel compounds with high selectivity to clear cell renal cell carcinoma (ccRCC) with common mutations. Using the GDSC databases, we searched for compounds with high selectivity for ccRCC with VHL and/or SETD2 mutations. Clinical impact and gene interactions were analysed using TCGA database. In vitro and in vivo studies were performed to validate the inhibitory effects of the compound. We identified the selective PI3Kβ inhibitor TGX221 as a selective inhibitor for ccRCC with both VHL and SETD2 mutations. TGX221 also targeted cancer cells with CDKN2A and PTEN mutations. Changes in PTEN and CDKN2A gene sets were associated with worsened prognosis of ccRCC. TGX221 substantially and selectively inhibited the down stream products of VHL, SETD2, and PTEN in ccRCC cells with VHL and SETD2 mutations. TGX221 also exhibited significant selectivity in inhibiting cell motility and tumourigenesis of ccRCC cells with VHL and SETD2 mutations. TGX221 is a novel inhibitor with high selectivity for ccRCC with VHL and SETD2 mutations. It also targeted PTEN and CDKN2A mutations. How those genes were associated with PI3Kβ warranted further investigations.
authors: Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
authors: Chenchen
authors: C
authors: Feng
authors: Brigham and Women's Hospital, Harvard Medical School, MA 02115, USA.
authors: Yang
authors: Y
authors: Sun
authors: Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
authors: Guanxiong
authors: G
authors: Ding
authors: Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
authors: Zhong
authors: Z
authors: Wu
authors: Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
authors: Haowen
authors: H
authors: Jiang
authors: Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
authors: Lujia
authors: L
authors: Wang
authors: Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
authors: Qiang
authors: Q
authors: Ding
authors: Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
authors: Hui
authors: H
authors: Wen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011744:Pyrimidinones / Q000494:pharmacology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011744:Pyrimidinones; D051881:Receptor, Notch1; C504718:TGX 221; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051059:PTEN Phosphohydrolase; C497446:VHL protein, human