Molecular design of dual inhibitors of PI3K and potential molecular target of cancer for its treatment: A review

Fimepinostat (CUDC‐907) in patients with relapsed/refractory diffuse large B cell and high‐grade B‐cell lymphoma: report of a phase 2 trial and exploratory biomarker analyses

(2021) Daniel J. Landsburg et al.   BRITISH JOURNAL OF HAEMATOLOGY

Design, Synthesis, and Pharmacological Evaluation of First‐in‐Class Multitarget N ‐Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors

(2020) Daniel A. Rodrigues et al.   ChemMedChem

CUDC‐907, a novel dual PI3K and HDAC inhibitor, in prostate cancer: Antitumour activity and molecular mechanism of action

(2020) Cheng Hu et al.   JOURNAL OF CELLULAR AND MOLECULAR MEDICINE

Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors

(2020) Ashish Thakur et al.   JOURNAL OF MEDICINAL CHEMISTRY

The PI3K/mTOR dual inhibitor GSK458 potently impedes ovarian cancer tumorigenesis and metastasis

(2020) Yangjiong Xiao et al.   CELLULAR ONCOLOGY

355TiP Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients (pts) with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2– LA/MBC)

(2020) N. Turner et al.   ANNALS OF ONCOLOGY

Multi-targeting Anticancer Agents: Rational Approaches, Synthetic Routes and Structure Activity Relationship

(2019) Harbinder Singh et al.   Anti-Cancer Agents in Medicinal Chemistry

Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia

(2019) Xinyu Li et al.   HAEMATOLOGICA

Design, Synthesis, and Biological Evaluation of 4-Methyl Quinazoline Derivatives as Anticancer Agents Simultaneously Targeting Phosphoinositide 3-Kinases and Histone Deacetylases

(2019) Kehui Zhang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Alpelisib: First Global Approval

(2019) Anthony Markham   DRUGS

Anticancer compound XL765 as PI3K/mTOR dual inhibitor: A structural insight into the inhibitory mechanism using computational approaches

(2019) Mohd Rehan   PLoS One

Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models

(2019) Simon P. Langdon et al.   Scientific Reports

Exploiting polypharmacology for improving therapeutic outcome of kinase inhibitors (KIs): An update of recent medicinal chemistry efforts

(2018) Xiaodong Ma et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, Synthesis, and Preclinical Evaluation of Fused Pyrimidine-Based Hydroxamates for the Treatment of Hepatocellular Carcinoma

(2018) Dizhong Chen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Prostate Power Play: Does Pik3ca Accelerate Pten -Deficient Cancer Progression?

(2018) Joanna Triscott et al.   Cancer Discovery

Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial

(2018) Jennifer R Brown et al.   Lancet Haematology

Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

(2018) Ewgenij Proschak et al.   JOURNAL OF MEDICINAL CHEMISTRY

Duvelisib: First Global Approval

(2018) Hannah A. Blair   DRUGS

Histone Deacetylase Inhibitors as Anticancer Drugs

(2017) Tomas Eckschlager et al.   INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

(2017) Florent Beaufils et al.   JOURNAL OF MEDICINAL CHEMISTRY

Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor‐Naïve Advanced Pancreatic Neuroendocrine Tumors

(2017) Ramon Salazar et al.   ONCOLOGIST

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies

(2017) Trisha M. Wise-Draper et al.   Targeted Oncology

PI3K/mTOR dual inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A synergistically exert anti-tumor activity in breast cancer

(2017) Liyan Chen et al.   Oncotarget

Combination therapy in combating cancer

(2017) Reza Bayat Mokhtari et al.   Oncotarget

Design, synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-c]quinazoline derivatives as novel phosphatidylinositol 3-kinase and histone deacetylase dual inhibitors

(2017) Yichao Wu et al.   RSC Advances

1230PDPHASE 1B STUDY OF ORAL DUAL-PI3K/MTOR INHIBITOR GDC-0980 IN COMBINATION WITH CARBOPLATIN (CARBO)/PACLITAXEL (PAC) ± BEVACIZUMAB (BEV) AND CISPLATIN (CIS)/PEMETREXED (PEM) IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS AND NSCLC

(2017) E. Calvo et al.   ANNALS OF ONCOLOGY

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2− advanced breast cancer (BELLE-4)

(2016) M. Martín et al.   ANNALS OF ONCOLOGY

Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma

(2016) Emmanuel Seront et al.   BJU INTERNATIONAL

New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation

(2016) Matthias Waldner et al.   BRITISH JOURNAL OF CLINICAL PHARMACOLOGY

Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)

(2016) William J. Scott et al.   ChemMedChem

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors

(2016) S. O. Dolly et al.   CLINICAL CANCER RESEARCH

Inhibition of autophagy enhances effects of PF-04691502 on apoptosis and DNA damage of lung cancer cells

(2016) Hong-Rong Fei et al.   INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY

Randomized Open-Label Phase II Trial of Apitolisib (GDC-0980), a Novel Inhibitor of the PI3K/Mammalian Target of Rapamycin Pathway, Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma

(2016) Thomas Powles et al.   JOURNAL OF CLINICAL ONCOLOGY

Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities

(2016) Yong Chen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K)

(2016) Marcian E. Van Dort et al.   JOURNAL OF MEDICINAL CHEMISTRY

Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial

(2016) Anas Younes et al.   LANCET ONCOLOGY

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

(2016) M. C. Smith et al.   MOLECULAR CANCER THERAPEUTICS

Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

(2016) Vanessa S. Rodrik-Outmezguine et al.   NATURE

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

(2016) Maria I. Carlo et al.   ONCOLOGIST

Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235

(2016) XIAOYU YANG et al.   Oncology Letters

Superior efficacy of co-treatment with the dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A against NSCLC

(2016) Junjie Piao et al.   Oncotarget

Probing the dynamic regulation of peripheral membrane proteins using hydrogen deuterium exchange-MS (HDX-MS)

(2015) O. Vadas et al.   BIOCHEMICAL SOCIETY TRANSACTIONS

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

(2015) Marcian E. Van Dort et al.   BIOORGANIC & MEDICINAL CHEMISTRY

The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the E -TCL1 mouse model

(2015) M. D. Blunt et al.   BLOOD

PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas

(2015) DEYU CHEN et al.   INTERNATIONAL JOURNAL OF ONCOLOGY

The PI3K/AKT Pathway and Renal Cell Carcinoma

(2015) Huifang Guo et al.   Journal of Genetics and Genomics

Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2

(2015) H. P. Soares et al.   MOLECULAR CANCER THERAPEUTICS

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

(2015) D. S. Mortensen et al.   MOLECULAR CANCER THERAPEUTICS

Dual PI3K/mTOR inhibitor, XL765 (SAR245409), shows superior effects to sole PI3K [XL147 (SAR245408)] or mTOR [rapamycin] inhibition in prostate cancer cell models

(2015) Giovanni Luca Gravina et al.   TUMOR BIOLOGY

PIK3CA mutation analysis in Chinese patients with surgically resected cervical cancer

(2015) Libing Xiang et al.   Scientific Reports

PI3K/mTOR Inhibition Markedly Potentiates HDAC Inhibitor Activity in NHL Cells through BIM- and MCL-1-Dependent Mechanisms In Vitro and In Vivo

(2014) M. Rahmani et al.   CLINICAL CANCER RESEARCH

Idelalisib: First Global Approval

(2014) Anthony Markham   DRUGS

Polypharmacology: the rise of multitarget drugs over combination therapies

(2014) Michela Rosini   Future Medicinal Chemistry

Dual Inhibition of Phosphatidylinositol 3′-Kinase and Mammalian Target of Rapamycin Using NVP-BEZ235 as a Novel Therapeutic Approach for Mucinous Adenocarcinoma of the Ovary

(2014) Akiko Kudoh et al.   INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER

New and emerging HDAC inhibitors for cancer treatment

(2014) Alison C. West et al.   JOURNAL OF CLINICAL INVESTIGATION

Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor

(2014) Dejan Juric et al.   NATURE

Dabrafenib in combination with trametinib for the treatment of metastatic melanoma

(2014) Mark M Awad et al.   Expert Review of Clinical Pharmacology

Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series

(2013) Hengmiao Cheng et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

NVP-BEZ235, Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor, Prominently Enhances Radiosensitivity of Prostate Cancer Cell Line PC-3

(2013) Wenjie Zhu et al.   CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS

Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer

(2013) Kamal S. Saini et al.   CANCER TREATMENT REVIEWS

mTOR in aging, metabolism, and cancer

(2013) Marion Cornu et al.   CURRENT OPINION IN GENETICS & DEVELOPMENT

Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials

(2013) Tianzhu Qiu et al.   Future Oncology

Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells

(2013) Erika Martinelli et al.   INTERNATIONAL JOURNAL OF CANCER

Preclinical evaluation of the PI3K-mTOR dual inhibitor PF-04691502 as a novel therapeutic drug in nasopharyngeal carcinoma

(2013) Chi Hang Wong et al.   INVESTIGATIONAL NEW DRUGS

Mutations in Critical Domains Confer the HumanmTORGene Strong Tumorigenicity

(2013) Avaniyapuram Kannan Murugan et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

MEK and the inhibitors: from bench to bedside

(2013) Akintunde Akinleye et al.   Journal of Hematology & Oncology

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

(2013) Y. Wang et al.   MOLECULAR CANCER THERAPEUTICS

PF-04691502 triggers cell cycle arrest, apoptosis and inhibits the angiogenesis in hepatocellular carcinoma cells

(2013) Feng-Ze Wang et al.   TOXICOLOGY LETTERS

Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors

(2012) B. Markman et al.   ANNALS OF ONCOLOGY

MEK Inhibition Leads to PI3K/AKT Activation by Relieving a Negative Feedback on ERBB Receptors

(2012) A. B. Turke et al.   CANCER RESEARCH

mTOR Signaling in Growth Control and Disease

(2012) Mathieu Laplante et al.   CELL

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

(2012) C. Qian et al.   CLINICAL CANCER RESEARCH

Integrative Survival-Based Molecular Profiling of Human Pancreatic Cancer

(2012) Timothy R. Donahue et al.   CLINICAL CANCER RESEARCH

Vertical inhibition of the PI3K/Akt/mTOR pathway for the treatment of osteoarthritis

(2012) Jiezhong Chen et al.   JOURNAL OF CELLULAR BIOCHEMISTRY

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

(2012) Keith T. Flaherty et al.   NEW ENGLAND JOURNAL OF MEDICINE

Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors

(2012) Geneviève P Delcuve et al.   Clinical Epigenetics

Polypharmacology: drug discovery for the future

(2012) A Srinivas Reddy et al.   Expert Review of Clinical Pharmacology

Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer

(2011) Daniel P. Sutherlin et al.   JOURNAL OF MEDICINAL CHEMISTRY

PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity

(2011) J. Yuan et al.   MOLECULAR CANCER THERAPEUTICS

Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide

(2011) G. Prasad et al.   NEURO-ONCOLOGY

The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation

(2011) Michelle C. Mendoza et al.   TRENDS IN BIOCHEMICAL SCIENCES

Vertical Targeting of the Phosphatidylinositol-3 Kinase Pathway as a Strategy for Treating Melanoma

(2010) S. A. Aziz et al.   CLINICAL CANCER RESEARCH

The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma

(2010) D. C. Cho et al.   CLINICAL CANCER RESEARCH

The PI3K Pathway As Drug Target in Human Cancer

(2010) Kevin D. Courtney et al.   JOURNAL OF CLINICAL ONCOLOGY

Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound26(PKI-587), a Highly Efficacious Dual Inhibitor

(2010) Aranapakam M. Venkatesan et al.   JOURNAL OF MEDICINAL CHEMISTRY

The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma

(2010) P M Bhende et al.   LEUKEMIA

mTOR: from growth signal integration to cancer, diabetes and ageing

(2010) Roberto Zoncu et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin

(2010) Steven D. Knight et al.   ACS Medicinal Chemistry Letters

The Emerging Role of the Phosphatidylinositol 3-Kinase/ Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cell Biology

(2010) Alberto M. Martelli et al.   Cancers

Phosphatidylinositol-3-Kinase as a Therapeutic Target in Melanoma

(2009) S. A. Aziz et al.   CLINICAL CANCER RESEARCH

NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations

(2008) V. Serra et al.   CANCER RESEARCH

An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer

(2008) K. Stemke-Hale et al.   CANCER RESEARCH

Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

(2008) S.-M. Maira et al.   MOLECULAR CANCER THERAPEUTICS

Network pharmacology: the next paradigm in drug discovery

(2008) Andrew L Hopkins   Nature Chemical Biology

Class I PI3K in oncogenic cellular transformation

(2008) L Zhao et al.   ONCOGENE

PI3K pathway alterations in cancer: variations on a theme

(2008) T L Yuan et al.   ONCOGENE