title: A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma.
abstract: Recent clinical trials have demonstrated targeting PI3K pathway is a promising strategy for the treatment of blood cancers. To identify novel PI3K inhibitors, we performed a high throughput virtual screen and identified several novel small molecule compounds, including PIK-C98 (C98). The cell-free enzymatic studies showed that C98 inhibited all class I PI3Ks at nano- or low micromolar concentrations but had no effects on AKT or mTOR activity. Molecular docking analysis revealed that C98 interfered with the ATP-binding pockets of PI3Ks by forming H-bonds and arene-H interactions with specific amino acid residues. The cellular assays demonstrated that C98 specifically inhibited PI3K/AKT/mTOR signaling pathway, but had no effects on other kinases and proteins including IGF-1R, ERK, p38, c-Src, PTEN, and STAT3. Inhibition of PI3K by C98 led to myeloma cell apoptosis. Furthermore, oral administration of C98 delayed tumor growth in two independent human myeloma xenograft models in nude mice but did not show overt toxicity. Pharmacokinetic analyses showed that C98 was well penetrated into myeloma tumors. Therefore, through a high throughput virtual screen we identified a novel PI3K inhibitor that is orally active against multiple myeloma with great potential for further development.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Man
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Qi
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D056004:Molecular Dynamics Simulation; D009101:Multiple Myeloma / Q000188:drug therapy; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013859:Thiocarbamates; C000600249:PIK-C98