title: RBx10080307, a dual EGFR/IGF-1R inhibitor for anticancer therapy.
abstract: Pharmacological intervention of epidermal growth factor receptor (EGFR) family members by antibodies or small molecule inhibitors has been one of the most successful approaches for anticancer therapy. However this therapy has its own limitations due to the development of resistance, over a period of time. One of the possible causes of the development of resistance to the therapy with EGFR inhibitors could be the simultaneous activation of parallel pathways. Both EGFR and insulin like growth factor-1 receptor (IGF-1R) pathways are reported to act reciprocal to each other and converge into the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibiting one pathway alone may therefore not be sufficient and could be a cause of development of resistance. The other cause could be mutations of EGFR which would be less sensitive to the inhibitors. We, therefore, suggest that co-targeting IGF-1R and EGFR kinases by dual inhibitors can lead to improved efficacy and address the problems of resistance. In the present manuscript, we report the identification of a novel, small molecule dual EGFR/IGF-1R inhibitor, RBx10080307 which displayed in vitro activity at the molecular level and oral efficacy in mouse xenograft model. The compound also showed in vitro activity in an EGFR mutant cell line and may thus have the potential to show activity in resistant conditions. Additional efficacy studies are needed in EGFR resistant mouse cancer model and if found efficacious, this can be a major advantage over standalone erlotinib and other existing therapies.
authors: Department of Pharmacology, Gurgaon, Haryana, India. ruchi.tandon.fg@dsin.co.in
authors: Ruchi
authors: R
authors: Tandon
authors: V
authors: V
authors: Senthil
authors: D
authors: D
authors: Nithya
authors: Venu
authors: V
authors: Pamidiboina
authors: Ankur
authors: A
authors: Kumar
authors: Sumit
authors: S
authors: Malik
authors: Tridib
authors: T
authors: Chaira
authors: Manish
authors: M
authors: Diwan
authors: Praful
authors: P
authors: Gupta
authors: R
authors: R
authors: Venkataramanan
authors: Renu
authors: R
authors: Malik
authors: Biswajit
authors: B
authors: Das
authors: Sunanda G
authors: SG
authors: Dastidar
authors: Ian
authors: I
authors: Cliffe
authors: Abhijit
authors: A
authors: Ray
authors: Pradip Kumar
authors: PK
authors: Bhatnagar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004355:Drug Stability; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D000077489:Piperazine; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C587987:N4-(3-cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-(4-(piperazin-1-yl)phenyl)pyrimidine-2,4-diamine; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D000077489:Piperazine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1