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Literature DB >> 24900721

Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics.

Meizhong Jin¹, Brenda A Petronella¹, Andy Cooke¹, Mridula Kadalbajoo¹, Kam W Siu¹, Andrew Kleinberg¹, Earl W May¹, Prafulla C Gokhale¹, Ryan Schulz¹, Jennifer Kahler¹, Mark A Bittner¹, Kenneth Foreman¹, Jonathan A Pachter¹, Robert Wild¹, David Epstein¹, Mark J Mulvihill¹.

Abstract

This letter describes a series of small molecule inhibitors of IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity and structure-kinetic relationships were elucidated and guided further optimizations within the series, culminating in compound 2. With an IGF-1R dissociative half-life (t 1/2) of >100 h, compound 2 demonstrated significant and extended PD effects in conjunction with tumor growth inhibition in xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties.

Entities: Disease Gene

Keywords: Insulin-like growth factor-1 receptor (IGF-1R); cancer; slow off-rate; time-dependent inhibition

Year: 2013 PMID： 24900721 PMCID： PMC4027544 DOI： 10.1021/ml400160a

Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345

17 in total

1. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.

Authors: Mark J Mulvihill; Andrew Cooke; Maryland Rosenfeld-Franklin; Elizabeth Buck; Ken Foreman; Darla Landfair; Matthew O'Connor; Caroline Pirritt; Yingchaun Sun; Yan Yao; Lee D Arnold; Neil W Gibson; Qun-Sheng Ji
Journal: Future Med Chem Date: 2009-09 Impact factor: 3.808

Review 2. The influence of drug-like concepts on decision-making in medicinal chemistry.

Authors: Paul D Leeson; Brian Springthorpe
Journal: Nat Rev Drug Discov Date: 2007-11 Impact factor: 84.694

Review 3. The importance of drug-target residence time.

Authors: Rumin Zhang; Frederick Monsma
Journal: Curr Opin Drug Discov Devel Date: 2009-07

Review 4. Small-molecule ATP-competitive dual IGF-1R and insulin receptor inhibitors: structural insights, chemical diversity and molecular evolution.

Authors: Meizhong Jin; Jing Wang; Elizabeth Buck; Mark J Mulvihill
Journal: Future Med Chem Date: 2012-03 Impact factor: 3.808

5. Discovery of an Orally Efficacious Imidazo[5,1-f][1,2,4]triazine Dual Inhibitor of IGF-1R and IR.

Authors: Meizhong Jin; Prafulla C Gokhale; Andy Cooke; Kenneth Foreman; Elizabeth Buck; Earl W May; Lixin Feng; Mark A Bittner; Mridula Kadalbajoo; Darla Landfair; Kam W Siu; Kathryn M Stolz; Douglas S Werner; Radoslaw S Laufer; An-Hu Li; Hanqing Dong; Arno G Steinig; Andrew Kleinberg; Yan Yao; Jonathan A Pachter; Robert Wild; Mark J Mulvihill
Journal: ACS Med Chem Lett Date: 2010-08-30 Impact factor: 4.345

6. Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy.

Authors: Meizhong Jin; Andrew Kleinberg; Andy Cooke; Prafulla C Gokhale; Kenneth Foreman; Hanqing Dong; Kam W Siu; Mark A Bittner; Kristen M Mulvihill; Yan Yao; Darla Landfair; Matthew O'Connor; Gilda Mak; Jonathan A Pachter; Robert Wild; Maryland Rosenfeld-Franklin; Qunsheng Ji; Mark J Mulvihill
Journal: Bioorg Med Chem Lett Date: 2010-12-23 Impact factor: 2.823

7. Novel 2-phenylquinolin-7-yl-derived imidazo[1,5-a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors.

Authors: Mark J Mulvihill; Qun-Sheng Ji; Heather R Coate; Andrew Cooke; Hanqing Dong; Lixin Feng; Kenneth Foreman; Maryland Rosenfeld-Franklin; Ayako Honda; Gilda Mak; Kristen M Mulvihill; Anthony I Nigro; Matthew O'Connor; Caroline Pirrit; Arno G Steinig; Kam Siu; Kathryn M Stolz; Yingchuan Sun; Paula A R Tavares; Yan Yao; Neil W Gibson
Journal: Bioorg Med Chem Date: 2007-10-23 Impact factor: 3.641

Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics.

1. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.

Review 2. The influence of drug-like concepts on decision-making in medicinal chemistry.

Review 3. The importance of drug-target residence time.

Review 4. Small-molecule ATP-competitive dual IGF-1R and insulin receptor inhibitors: structural insights, chemical diversity and molecular evolution.

5. Discovery of an Orally Efficacious Imidazo[5,1-f][1,2,4]triazine Dual Inhibitor of IGF-1R and IR.

6. Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy.

7. Novel 2-phenylquinolin-7-yl-derived imidazo[1,5-a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors.

8. Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers.

9. A prospective study of plasma C-peptide and colorectal cancer risk in men.

Review 10. The insulin-like growth factor system and cancer.

1. A structure-kinetic relationship study using matched molecular pair analysis.

Review 2. Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers.