Design and synthesis of close analogs of LCRF-0004, a potent and selective RON receptor tyrosine kinase inhibitor

Raeppel, Stéphane; Raeppel, Franck; Therrien, Éric

doi:10.1016/j.bmcl.2015.04.056

Cited by 18 publications

(11 citation statements)

References 24 publications

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“…Due to the high degree of similarity in the kinase domains of MET and RON, available SMIs often show dual inhibitory effect with slightly different IC 50 values (Yan et al 2013;Yao et al 2013a;Chang et al 2015). To our knowledge, BMS-777607 and LCRF-0004 are the only SMIs reported to inhibit RON at lower IC 50 than Met (Schroeder et al 2009;Raeppel et al 2010Raeppel et al , 2015. BMS-777607/ASLAN002 has shown very promising results in preclinical models of breast, pancreatic, prostate, and colorectal cancer and has recently finished phase I clinical trials (Dai and Siemann 2010;Eyob et al 2013a;Zeng et al 2014;Bieniasz et al 2015;Andrade et al 2017).…”

Section: Strategies For Targeting Ron For Cancer Therapymentioning

confidence: 95%

RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers

Faham

Welm

2016

Cold Spring Harb Symp Quant Biol

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With an increasing body of literature covering RON receptor tyrosine kinase function in different types of human cancers, it is becoming clear that RON has prominent roles in both cancer cells and in the tumor-associated microenvironment. RON not only activates several oncogenic signaling pathways in cancer cells, leading to more aggressive behavior, but also promotes an immunosuppressive, alternatively activated phenotype in macrophages and limits the antitumor immune response. These two unique functions of this oncogene, the strong correlation between RON expression and poor outcomes in cancer, and the high tolerability of a new RON inhibitor make it an exciting therapeutic target, the blocking of which offers an advantage toward improving the survival of cancer patients. Here, we discuss recent findings on the role of RON signaling in cancer progression and its potential in cancer therapy.

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Section: Strategies For Targeting Ron For Cancer Therapymentioning

confidence: 95%

RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers

Faham

Welm

2016

Cold Spring Harb Symp Quant Biol

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“…2‐Alkoxy‐2,3‐dihydrofurans tended to form furans under acidic conditions by eliminating an alcohol . However, in the presence of a primary amine, pyrrole derivative 163 will be formed instead of furan (Scheme ) . This means that cleavage of the endocyclic C−O bond occurred, and the formed intermediate ( VIII ) act as a 1,4‐dicarbonyl component of Paal–Knoor reaction to form pyrrole.…”

Section: Masked Axb3 Smentioning

confidence: 99%

Aldo‐X Bifunctional Building Blocks for the Synthesis of Heterocycles

Ravichandiran

Lai

2016

The Chemical Record

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Compounds containing oxygen, nitrogen, or sulfur atoms inside the rings are attracting much attention and interest due to their biological importance. In recent years, several methods for the synthesis of such molecules have been reported by using aldo-X bifunctional building blocks (AXB3 s) as substrates; these are a wide class of organic molecules that contain at least two reactive sites, among them, one aldehyde, acetal, or semiacetal group was involved. Because of the multiple reactivities, AXB3 s are widely used in the one-pot synthesis of biologically important heterocycles. This review summarizes the synthesis of important heterocycles by using AXB3 s as pivotal components in establishing multicomponent reactions, tandem reactions, and so forth. In many cases, the established reaction systems with AXB3 s were characterized by some green properties, such as easy access to the substrate, mild and environmentally benign conditions, and wide scope of the substrate.

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“…10 Devoid of experimental structural information about the binding mode of LCRF-0004 within the RON and/or c-Met kinase domains, we deemed important to synthesize and evaluate few constrained analogs of LCRF-0004 to elucidate its bioactive conformation when bound in the active site of RON enzyme. Thus, we evaluated new bicyclic head groups (Fig.…”

Section: Introductionmentioning

confidence: 99%