Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors

Raeppel, Stéphane; Therrien, Éric; Raeppel, Franck

doi:10.1016/j.bmcl.2015.06.034

Cited by 11 publications

(4 citation statements)

References 27 publications

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“…Combined inhibition of MST1R (RON)/MET/Tyro3 and Axl is superior to inhibition of MST1R (RON) alone, with survival remaining undefined for the 25 mg/kg dose of BMS-777607. The drug optimization of LCRF-0004 is still ongoing and several new analogs have been disclosed (57–59).…”

Section: Discussionmentioning

confidence: 99%

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

et al. 2019

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Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro , however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.

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Section: Discussionmentioning

confidence: 99%

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

et al. 2019

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“…[33] The docking procedure was guided based on the predicted binding mode of LCRF-0004 with the modeled RON kinase domain. To this end, a geometric center was assigned based on the important amino acids in the binding pocket of RON (i. e. Glu 1131 , Met 1135 , Leu 1144 , Leu 1161 , Pro 1162 , Met 1164 , Gly 1167 , Ala 1225 , Phe 1204 , Met 1215 , Asp 1226 , Phe 1227 , and Gly 1228 ) [17,34] and set as the center of the binding site. All atoms within a 10 Å radius were selected for molecular docking of selected compounds by applying the default settings in GOLD program.…”

Section: Molecular Dockingmentioning

confidence: 99%

Ligand‐based Discovery of Novel Small Molecule Inhibitors of RON Receptor Tyrosine Kinase

Zarei

Faham

Vankayalapati

et al. 2020

Molecular Informatics

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Background: RON (Recepteur d′Origine Nantais) receptor tyrosine kinase is a promising target for anti‐cancer therapeutics. The aim of this study was to identify new RON inhibitors using virtual screening methods. Methods: To this end, a ligand‐based virtual screening approach was employed for screening of ZINC database on the homology model of RON receptor. All the selected hits were inspected in terms of drug‐likeness, ADME properties, and toxicity profiles. Ligand‐based similarity searches along with further filtering criteria led to the identification of two compounds, TKI1 and TKI2 that were evaluated using in vitro cell‐based RON inhibition assays. Results: The results showed that TKI1 and TKI2 could reduce phosphorylation of RON. Both compounds showed inhibitory activity of the downstream mTOR pathway with no apparent effects on other signaling mediators in a dose‐dependent manner. Conclusion: These compounds can provide a basis for developing novel anti‐RON inhibitors applicable to cancer therapy using medicinal chemistry‐oriented optimization strategies.

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“…Досить цікавим видається синтез піразолодіа-зепіну 81 -аналога потужного інгібітора тиро-зинкінази RON [49,50]. Як і у попередньому варі-анті в ролі циклізуючого реагенту використову-вався хлорацетилхлорид, одначе вихідними суб-стратами були аміноаміди 82.…”

Section: піразоло[43-e][14]діазепін-8-ониunclassified

“…Як і у попередньому варі-анті в ролі циклізуючого реагенту використову-вався хлорацетилхлорид, одначе вихідними суб-стратами були аміноаміди 82. Це, у свою чергу, дозволило у дві стадії (ацилювання аміноаміду хлорацетилхлоридом та внутрішньомолекуляр-на циклізація в ДМФА) отримати цільовий про-дукт 81, екзофункціоналізований по положенню 5 піразолодіазепінової системи [49][50][51] На схемі 31 по-казано хімізм одного із них, який включає взає-модію аміду 5-аміноімідазолу 112 із гліколевим альдегідом через перегрупування Амадорі. Реак-цію зазвичай проводять у фосфатному буфері при 60 °С впродовж 24 год, а продукт очищають шля-хом твердофазної екстракції з іонообмінної смо-ли [64].…”

Section: піразоло[43-e][14]діазепін-8-ониunclassified

2-amino-5-(4-chloro-1h-imidazol-5-yl)-1,3,4-thiadiazoles: synthesis, pyrimidoannulation and the bactericidal activity

Grozav¹,

Chornous²,

Gavrylyuk³

et al. 2013

J. org. pharm. chem.

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2 ТОВ «НВП «Єнамін» 3 НТУУ «Київський політехнічний інститут ім. Ігоря Сікорського» Азоло[1,4]діазепіни: методи синтезу та структурна модифікаціяУзагальнені та систематизовані літературні джерела, які стосуються методів синтезу та хімічних перетво-рень відомих на теперішній час азоло [1,4]діазепінів: піразоло-, імідазо-, триазоло-, ізоксазоло-, оксазоло-, ізотіазоло-та тіазолодіазепінів. Значна увага приділена піразоло [1,4]діазепінам як найбільш досліджено-му типу азолодіазепінових систем. Відзначена їх роль як важливих субстанцій для дизайну сполук із по-тужним фармакологічним потенціалом. Детально розглянуті методи синтезу піразоло [3,4-e]

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Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors

Cited by 11 publications

References 27 publications

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

When RON MET TAM in Mesothelioma: All Druggable for One, and One Drug for All?

Ligand‐based Discovery of Novel Small Molecule Inhibitors of RON Receptor Tyrosine Kinase

2-amino-5-(4-chloro-1h-imidazol-5-yl)-1,3,4-thiadiazoles: synthesis, pyrimidoannulation and the bactericidal activity

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