生物活性

• 描述Chk1 (Checkpoint kinase 1), an important serine/threonine kinase, is responding to DNA damage and stall DNA replication. Chk1 plays a key role in maintaining the replication fork viability during exposure to DNA antimetabolites. Inhibition of Chk1 will lead to accumulation of double-strand DNA breaks and cell death in human tumor cell lines exposure to antimetabolite. GDC-0575 is a selective Chk1 inhibitor with IC50 value of 1.2 nM^[1]. GDC-0575 exhibited anti-proliferative effect on nine of ten soft-tissue sarcoma (STS) cell lines with IC50 values ranging in 0.025-5.9μM, with inhibition of the phosphorylation of Ser296 observed. GDC-0575 could synergy with gemcitabine. It abrogated DNA damage-induced S and G2–M checkpoints exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Combined therapy of GDC-0575 (25mg/kg, orally) with gemcitabine twice a week for 3 weeks significantly reduced tumor growth increased progression-free survival of a P53mut UPS PDX model^[2]. GDC-0575 could enhance AraC-mediated killing of AML cells both in vitro and in vivo with abrogation of any potential chemoresistance mechanisms involving DNA repair^[1].

• 动物研究
  剂量	Mice: 25 mg/kg - 50 mg/kg[2] (p.o.), 7.5 mg/kg[3] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01564251	Lymphoma, Solid Tumor	Phase 1	Completed	-	United States, Connecticut ... more >> Yale Cancer Center New Haven, Connecticut, United States, 06520 United States, Massachusetts Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215 United States, Michigan Karmanos Cancer Institute Detroit, Michigan, United States, 48201 United States, Oklahoma University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma, United States, 73104 United States, Tennessee The Sarah Cannon Research Inst Nashville, Tennessee, United States, 37203 France Institut Bergonie; Oncologie Bordeaux, France, 33076 Institut Gustave Roussy; Departement Oncologie Medicale Villejuif, France, 94805 Collapse <<
  NCT02324998	Prostate Cancer	Phase 1	Recruiting	July 2018	United Kingdom ... more >> Addenbrooke's Hospital, Cambridge University Hospitals Foundation Trust, Recruiting Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ Contact: Ruth Tysoe, BSc.    01223 348089    ruth.tysoe@addenbrookes.nhs.uk    Contact: Simon Pacey, MRCP, Ph.D    01223 769 480    scp46@medschl.cam.ac.uk Collapse <<
  NCT02203513	Ovarian Cancer ... more >> Breast Cancer Prostate Cancer Collapse <<	Phase 2	Recruiting	June 30, 2020	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting Bethesda, Maryland, United States, 20892 Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937 Collapse <<

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