Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies

Phase I dose-escalation study of AZD7762 in combination with gemcitabine (gem) in patients (pts) with advanced solid tumors.

(2017) E. A. Sausville et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase I, open-label, dose-escalation study of AZD7762 in combination with irinotecan (irino) in patients (pts) with advanced solid tumors.

(2017) A. L. Ho et al.   JOURNAL OF CLINICAL ONCOLOGY

Abstract 779: ARF activation is responsible for the tumor-suppressing function of p53 in basal cell carcinomas (BCCs) in Ptch1+/- mice.

(2014) Grace Y. Wang et al.   CANCER RESEARCH

Synthesis and evaluation of debromohymenialdisine-derived Chk2 inhibitors

(2012) Rahman Shah Zaib Saleem et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography

(2012) Cornelis Matijssen et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors

(2012) Vibha Oza et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Pyridyl aminothiazoles as potent Chk1 inhibitors: Optimization of cellular activity

(2012) Vadim Y. Dudkin et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Pyridyl aminothiazoles as potent inhibitors of Chk1 with slow dissociation rates

(2012) Vadim Y. Dudkin et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer

(2012) Cynthia X. Ma et al.   BREAST CANCER RESEARCH AND TREATMENT

Enhancing CHK1 inhibitor lethality in glioblastoma

(2012) Yong Tang et al.   CANCER BIOLOGY & THERAPY

Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition

(2012) Amy D Guertin et al.   Cancer Cell International

Combined inhibition of Chk1 and Wee1: In vitro synergistic effect translates to tumor growth inhibition in vivo

(2012) Laura Carrassa et al.   CELL CYCLE

CCT244747 Is a Novel Potent and Selective CHK1 Inhibitor with Oral Efficacy Alone and in Combination with Genotoxic Anticancer Drugs

(2012) M. I. Walton et al.   CLINICAL CANCER RESEARCH

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m2 every 21 days in patients with cancer

(2012) Glen J. Weiss et al.   INVESTIGATIONAL NEW DRUGS

Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors

(2012) Michael Lainchbury et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Checkpoint Kinase Inhibitor (S)-5-(3-Fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by Structure-Based Design and Optimization of Thiophenecarboxamide Ureas

(2012) Vibha Oza et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

(2012) Xiaohua Huang et al.   ACS Medicinal Chemistry Letters

Radioprotection by Hymenialdisine-Derived Checkpoint Kinase 2 Inhibitors

(2011) Thu N. T. Nguyen et al.   ACS Chemical Biology

Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy

(2011) Heekyoung Yang et al.   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Chk1 inhibition and Wee1 inhibition combine synergistically to impede cellular proliferation

(2011) Kurtis D. Davies et al.   CANCER BIOLOGY & THERAPY

Hallmarks of Cancer: The Next Generation

(2011) Douglas Hanahan et al.   CELL

Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase

(2011) Samuel McNeely et al.   CELL CYCLE

Therapeutic Implications for the Induced Levels of Chk1 in Myc-Expressing Cancer Cells

(2011) A. Hoglund et al.   CLINICAL CANCER RESEARCH

Current Inhibitors of Checkpoint Kinase 2

(2011) T. N.T. Nguyen et al.   CURRENT MEDICINAL CHEMISTRY

Targeting the S and G2 checkpoint to treat cancer

(2011) Tao Chen et al.   DRUG DISCOVERY TODAY

Checkpoint kinase inhibitors: a patent review (2009 – 2010)

(2011) Michael Lainchbury et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

(2011) John C. Reader et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structural characterization of inhibitor complexes with checkpoint kinase 2 (Chk2), a drug target for cancer therapy

(2011) George T. Lountos et al.   JOURNAL OF STRUCTURAL BIOLOGY

Targeting the Replication Checkpoint Using SCH 900776, a Potent and Functionally Selective CHK1 Inhibitor Identified via High Content Screening

(2011) T. J. Guzi et al.   MOLECULAR CANCER THERAPEUTICS

Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors

(2011) Matilde Murga et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells

(2011) P T Ferrao et al.   ONCOGENE

The Expression of DNA Damage Checkpoint Proteins and Prognostic Implication in Metastatic Brain Tumors

(2011) Ho Jun Seol et al.   ONCOLOGY RESEARCH

Single-Agent Inhibition of Chk1 Is Antiproliferative in Human Cancer Cell Lines In Vitro and Inhibits Tumor Xenograft Growth In Vivo

(2011) Kurtis D. Davies et al.   ONCOLOGY RESEARCH

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma

(2011) K. A. Cole et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Anticancer therapy with checkpoint inhibitors: what, where and when?

(2011) Michelle D. Garrett et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases

(2010) Thomas P. Matthews et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Discovery of a novel class of triazolones as Checkpoint Kinase inhibitors—Hit to lead exploration

(2010) Vibha Oza et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Design, synthesis and SAR of thienopyridines as potent CHK1 inhibitors

(2010) Lianyun Zhao et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach—Part 1

(2010) Michael P. Dwyer et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies

(2010) Paula M. Fracasso et al.   CANCER CHEMOTHERAPY AND PHARMACOLOGY

Mechanism of Radiosensitization by the Chk1/2 Inhibitor AZD7762 Involves Abrogation of the G2Checkpoint and Inhibition of Homologous Recombinational DNA Repair

(2010) Meredith A. Morgan et al.   CANCER RESEARCH

In vitro and In vivo Radiation Sensitization of Human Tumor Cells by a Novel Checkpoint Kinase Inhibitor, AZD7762

(2010) J. B. Mitchell et al.   CLINICAL CANCER RESEARCH

New Insights into Checkpoint Kinase 1 in the DNA Damage Response Signaling Network

(2010) Y. Dai et al.   CLINICAL CANCER RESEARCH

Tumor Suppressor CHK2: Regulator of DNA Damage Response and Mediator of Chromosomal Stability

(2010) A. Stolz et al.   CLINICAL CANCER RESEARCH

A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial

(2010) Tianhong Li et al.   INVESTIGATIONAL NEW DRUGS

Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

(2010) John J. Caldwell et al.   JOURNAL OF MEDICINAL CHEMISTRY

The Preclinical Pharmacology and Therapeutic Activity of the Novel CHK1 Inhibitor SAR-020106

(2010) M. I. Walton et al.   MOLECULAR CANCER THERAPEUTICS

Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics

(2010) Cynthia X. Ma et al.   TRENDS IN MOLECULAR MEDICINE

Characterization of the CHK1 Allosteric Inhibitor Binding Site

(2009) Darin Vanderpool et al.   BIOCHEMISTRY

Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2

(2009) Stephen Hilton et al.   BIOORGANIC & MEDICINAL CHEMISTRY

A phase I trial of UCN-01 and prednisone in patients with refractory solid tumors and lymphomas

(2009) Shivaani Kummar et al.   CANCER CHEMOTHERAPY AND PHARMACOLOGY

Constitutive Activation of the DNA Damage Signaling Pathway in Acute Myeloid Leukemia with Complex Karyotype: Potential Importance for Checkpoint Targeting Therapy

(2009) C. Cavelier et al.   CANCER RESEARCH

Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2

(2009) H Christian Reinhardt et al.   CURRENT OPINION IN CELL BIOLOGY

Identification of Inhibitors of Checkpoint Kinase 1 through Template Screening

(2009) Thomas P. Matthews et al.   JOURNAL OF MEDICINAL CHEMISTRY

Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation

(2009) Fabio Zuccotto et al.   JOURNAL OF MEDICINAL CHEMISTRY

Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid  -amide]

(2009) A. G. Jobson et al.   JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer

(2009) David O Azorsa et al.   Journal of Translational Medicine

Atomic resolution structure of the cytoplasmic domain ofYersinia pestisYscU, a regulatory switch involved in type III secretion

(2009) George T. Lountos et al.   PROTEIN SCIENCE

Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors

(2008) James W. Janetka et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Development of thioquinazolinones, allosteric Chk1 kinase inhibitors

(2008) Antonella Converso et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Keeping checkpoint kinases in line: new selective inhibitors in clinical trials

(2008) Susan Ashwell et al.   EXPERT OPINION ON INVESTIGATIONAL DRUGS

Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1

(2008) A. Blasina et al.   MOLECULAR CANCER THERAPEUTICS

AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies

(2008) S. D. Zabludoff et al.   MOLECULAR CANCER THERAPEUTICS