Structure-based design of molecular cancer therapeutics

The Hallmarks of Cancer

2000 • 27,569 citations

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1

2001 • 16,438 citations

EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy

2004 • 9,201 citations

The Protein Kinase Complement of the Human Genome

2002 • 7,708 citations

Surfing the p53 network

2000 • 6,487 citations

The Phosphoinositide 3-Kinase Pathway

2002 • 5,427 citations

In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2

2004 • 4,416 citations

EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib

2004 • 4,293 citations

Cancer genes and the pathways they control

2004 • 4,172 citations

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

2005 • 3,292 citations

Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF

2004 • 2,674 citations

Protein kinases — the major drug targets of the twenty-first century?

2002 • 2,101 citations

The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

2008 • 1,886 citations

Reaching for high-hanging fruit in drug discovery at protein–protein interfaces

2007 • 1,878 citations

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

2008 • 1,820 citations

Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor

2004 • 1,785 citations

Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase

2000 • 1,770 citations

Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors

1999 • 1,640 citations

Structure of Bcl-x _L -Bak Peptide Complex: Recognition Between Regulators of Apoptosis

1997 • 1,429 citations

Crystal Structure of an Hsp90–Geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent

1997 • 1,345 citations

Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor

2002 • 1,308 citations

G-protein-coupled receptors and cancer

2007 • 1,308 citations

Identification and Structural Characterization of the ATP/ADP-Binding Site in the Hsp90 Molecular Chaperone

1997 • 1,235 citations

Protein Kinase Inhibitors: Insights into Drug Design from Structure

2004 • 1,180 citations

Structural Determinants of Phosphoinositide 3-Kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine

2000 • 1,121 citations

A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling

2006 • 1,119 citations

Regulation of Protein Kinases

2004 • 1,103 citations

Crystal structure of the tyrosine kinase domain of the human insulin receptor

1994 • 1,071 citations

A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)

2004 • 1,066 citations

Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity

2007 • 1,061 citations

In vitro Activity of Bcr-Abl Inhibitors AMN107 and BMS-354825 against Clinically Relevant Imatinib-Resistant Abl Kinase Domain Mutants

2005 • 1,039 citations

A decade of fragment-based drug design: strategic advances and lessons learned

2007 • 1,023 citations

Rational design of inhibitors that bind to inactive kinase conformations

2006 • 1,013 citations

Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin

1999 • 979 citations

Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571).

2002 • 925 citations

Fragment-based lead discovery

2004 • 773 citations

Oncogene Addiction

2008 • 744 citations

The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer

2008 • 722 citations

Structural biology of the Bcl-2 family of proteins

2003 • 706 citations

Structural Snapshots of Human HDAC8 Provide Insights into the Class I Histone Deacetylases

2004 • 662 citations

Structure-Based Design of Spiro-oxindoles as Potent, Specific Small-Molecule Inhibitors of the MDM2−p53 Interaction

2006 • 655 citations

Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition

2008 • 646 citations

The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants

2006 • 645 citations

Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase

2004 • 598 citations

Recent Developments in Fragment-Based Drug Discovery

2008 • 595 citations

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition

2004 • 588 citations

Class I PI3K in oncogenic cellular transformation

2008 • 557 citations

Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises

2008 • 531 citations

The Structure of a Human p110α/p85α Complex Elucidates the Effects of Oncogenic PI3Kα Mutations

2007 • 523 citations

Drugging the Cancer Chaperone HSP90

2007 • 511 citations

Histone Deacetylase Inhibitors

2003 • 501 citations

Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors

2007 • 480 citations

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008 • 462 citations

Can we rationally design promiscuous drugs?

2006 • 461 citations

NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis

2008 • 461 citations

The Hsp90 molecular chaperone: an open and shut case for treatment

2008 • 440 citations

Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets

2007 • 431 citations

4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer

2007 • 424 citations

Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate p53 in Cells

2005 • 419 citations

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases

2008 • 419 citations

Fragment-Based Lead Discovery Using X-ray Crystallography

2004 • 408 citations

Three-dimensional structures of H-ras p21 mutants: Molecular basis for their inability to function as signal switch molecules

1990 • 395 citations

Rationale for Bcl‐X_L/Bad peptide complex formation from structure, mutagenesis, and biophysical studies

2000 • 388 citations

New approaches to molecular cancer therapeutics

2006 • 382 citations

Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors

2008 • 375 citations

Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases

2007 • 354 citations

Keynote review: Structural biology and drug discovery

2005 • 327 citations

Discovering novel ligands for macromolecules using X-ray crystallographic screening

2000 • 313 citations

Virtual Exploration of the Small‐Molecule Chemical Universe below 160 Daltons

2005 • 307 citations

Targeted therapy for cancer using PARP inhibitors

2008 • 282 citations

Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-x_L from NMR and Parallel Synthesis

2005 • 281 citations

Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins

2008 • 279 citations

Epidermal growth factor receptor tyrosine kinase

1994 • 258 citations

Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms

2004 • 255 citations

Novel, Potent Small-Molecule Inhibitors of the Molecular Chaperone Hsp90 Discovered through Structure-Based Design

2005 • 231 citations

Using structure to define the function of phosphoinositide 3‐kinase family members

1997 • 230 citations

Overexpression of G protein-coupled receptors in cancer cells: Involvement in tumor progression

2005 • 230 citations

The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors

2005 • 221 citations

Distinct Structural Mechanisms for Inhibition of Pyruvate Dehydrogenase Kinase Isoforms by AZD7545, Dichloroacetate, and Radicicol

2007 • 212 citations

Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models

2008 • 197 citations

Inhibitor and NAD⁺ Binding to Poly(ADP-ribose) Polymerase As Derived from Crystal Structures and Homology Modeling^,

1998 • 196 citations

Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110α inhibitors

2006 • 188 citations

Protein–protein interactions and cancer: small molecules going in for the kill

2005 • 167 citations

Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery

2006 • 164 citations

Knowledge Based Prediction of Ligand Binding Modes and Rational Inhibitor Design for Kinase Drug Discovery

2008 • 159 citations

Fragment-based lead discovery: a chemical update

2006 • 145 citations

AstexViewer: a visualisation aid for structure-based drug design.

2002 • 145 citations

PARP Inhibitor Development for Systemic Cancer Targeting

2007 • 140 citations

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

2007 • 139 citations

Pharmaceutical research in molecular oncology

1994 • 134 citations

Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery

2007 • 133 citations

Structural Biology and Drug Discovery

2006 • 131 citations

Novel Tricyclic Poly(ADP-ribose) Polymerase-1 Inhibitors with Potent Anticancer Chemopotentiating Activity: Design, Synthesis, and X-ray Cocrystal Structure

2002 • 130 citations

Small molecular weight protein–protein interaction antagonists—an insurmountable challenge?

2008 • 127 citations

SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors

2005 • 126 citations

Do molecularly targeted agents in oncology have reduced attrition rates?

2008 • 124 citations

Small Molecule Inhibitors of Protein–Protein Interactions

2012 • 119 citations

Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies

2000 • 119 citations

In vitro Biological Characterization of a Novel, Synthetic Diaryl Pyrazole Resorcinol Class of Heat Shock Protein 90 Inhibitors

2007 • 110 citations

Phosphoinositide 3-kinases as drug targets in cancer

2005 • 105 citations

Structural biology in drug design: selective protein kinase inhibitors

2002 • 100 citations

Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration

2008 • 95 citations

Clinical anticancer drug development: targeting the cyclin-dependent kinases

2004 • 94 citations

Drug discovery and p53

2003 • 86 citations

A Structural Comparison of Inhibitor Binding to PKB, PKA and PKA-PKB Chimera

2007 • 84 citations

Therapeutic strategies for inhibiting oncogenic BRAF signaling

2008 • 77 citations

Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma

2009 • 77 citations

Shooting at survivors: Bcl-2 family members as drug targets for cancer

2003 • 61 citations

Rapid Evolution of 6-Phenylpurine Inhibitors of Protein Kinase B through Structure-Based Design

2007 • 60 citations

Design and Crystal Structures of Protein Kinase B-Selective Inhibitors in Complex with Protein Kinase A and Mutants

2004 • 57 citations

Mutants of Protein Kinase A that Mimic the ATP-binding Site of Protein Kinase B (AKT)

2003 • 50 citations

Genomics and the second golden era of cancer drug development

2005 • 47 citations

Design, Synthesis, and Evaluation of 3,4-Dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as Inhibitors of Poly(ADP-Ribose) Polymerase

2004 • 44 citations

Structural genomics and drug discovery: all in the family

2008 • 42 citations

Doing more than just the structure—structural genomics in kinase drug discovery

2008 • 39 citations

Small-Molecule Inhibitors of Protein-Protein Interactions

2011 • 37 citations

Histone Deacetylase Inhibitors in Cancer Therapy: Latest Developments, Trends and Medicinal Chemistry Perspective

2007 • 30 citations

Design of Selective Thrombin Inhibitors Based on the (R)-Phe-Pro-Arg Sequence

2002 • 21 citations

Targeting the cancer chaperone HSP90

2007 • 11 citations