Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors

Ng, Pearly Shuyi; Foo, Klement; Sim, Sandra Phek Lin; Wang, Gang; Huang, Chuhui; Li, Tan; Poulsen, Anders; Liu, Boping; Tee, Doris Hui Ying; Ahmad, Nur Huda Binte; Wang, Sifang; Zhao, Ke; Lee, May Ann; Kwek, Zekui Perlyn; Joy, Joma; Anantharajan, Jothi; Baburajendran, Nithya; Pendharkar, Vishal; Manoharan, Vithya; Vuddagiri, Susmitha; Sangthongpitag, Kanda; Hill, Jeffrey; Keller, Thomas H.; Hung, Alvin W.

doi:10.1016/j.bmc.2021.116437

Cited by 8 publications

(5 citation statements)

References 50 publications

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“…However, there are no table entries for papers targeting proteases, the first time this target class has not been represented. In contrast, there are more examples of GPCR case studies in Table than in previous years (entries 26, 27, and 28), including the description of the discovery of the M1 agonist clinical compound HTL9936 (entry 28). …”

Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Walsh¹,

Erlanson²,

Esch

et al. 2023

J. Med. Chem.

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This Perspective is the seventh in an annual series that summarizes successful Fragment-to-Lead (F2L) case studies published in a given year. A tabulated summary of relevant articles published in 2021 is provided, and features such as target class, screening methods, and ligand efficiency are discussed, both for the 2021 examples and for the combined examples over the years 2015−2021. In addition, trends and new developments in the field are summarized. In particular, the use of structural information in fragment-based drug discovery is discussed.

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Section: Resultsmentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Walsh¹,

Erlanson²,

Esch

et al. 2023

J. Med. Chem.

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“…It is becoming increasingly evident that S-protein may impact cellular biology independent of interactions with the ACE2 receptor. Recently, there have been reports that the SARS-CoV-2 S protein interacts with other receptors such as neurophilin-1, ( 16 ), CD147 ( 17 ), tyrosine-protein kinase receptor UFO (AXL) ( 18 , 19 ), ASGR1 and KREMEN1 ( 20 ), and others. In addition, the S-protein induces innate immune activation via Toll-like receptors TLR2 and TLR4 ( 24 , 25 , 27 , 64 ) and in silico modeling suggests that it may direct interact with TLRs ( 65 ).…”

Section: Discussionmentioning

confidence: 99%

“…The pathophysiology and immune response to SARS-CoV-2 infection are broad and involve signaling pathways from several cell and tissue types ( 15 ). In particular, although it is understood that SARS-CoV-2 used S-protein binding to ACE2 to enter cells, it is now increasingly reported that it binds to other receptors such as neurophilin-1, ( 16 ), CD147 ( 17 ), tyrosine-protein kinase receptor UFO (AXL) ( 18 , 19 ), ASGR1, KREMEN1 ( 20 ), and others. Viral genetic material activates TLR7, and there have been several reports linking TLR7 deficiency with severe outcomes in COVID-19 ( 21 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

The SARS-CoV-2 spike S1 protein induces global proteomic changes in ATII-like rat L2 cells that are attenuated by hyaluronan

Mobley

Molyvdas

Kojima

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

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The COVID-19 pandemic continues to impose a major impact on global health and economy since its identification in early 2020, causing significant morbidity and mortality worldwide. Caused by the SARS-CoV-2 virus, along with a growing number of variants, COVID-19 has led to 651,918,402 confirmed cases, and 6,656,601 deaths worldwide (as of December 27, 2022; https://covid19.who.int/). Despite advances in our understanding of COVID19 pathogenesis, the precise mechanism by which SARS-CoV2 causes epithelial injury is incompletely understood. In this current study, robust application of global-discovery proteomics identified highly significant induced changes by the Spike S1 protein of SARS-CoV-2 in the proteome of alveolar type II (ATII)-like Rat L2 cells that lack ACE2 receptors. Systems biology analysis revealed that the S1 induced proteomics changes were associated with three significant network hubs: E2F1, CREB1/ RelA, and ROCK2/ RhoA. We also found that pre-treatment of L2 cells with High Molecular Weight Hyaluronan (HMW-HA), greatly attenuated the S1 effects on the proteome. Western blotting analysis and cell cycle measurements confirmed the S1-upregulation of E2F1 and ROCK2/RhoA in L2 cells and the protective effects of HMW-HA. Taken as a whole, our studies revealed profound and novel biological changes that contribute to our current understanding of both S1 and Hyaluronan biology. This data shows that the S1 protein may contribute to epithelial injury induced by SARS-CoV-2. In addition, our work supports the potential benefit of HMW-HA in ameliorating SARS CoV2 induced cell injury (236 words).

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“…The in vitro AXL enzymatic assay was performed using the method previously reported 61 . The reaction was performed in the buffer containing 100 mM Hepes, pH 7.5, 10 mM MgCl 2 , 1 × Halt™ Protease and Phosphatase Inhibitor Cocktail, EDTA-Free, 1 mM DTT (Dithiothreitol), 0.003% of Brij35 and 0.004% of Tween-20.…”

Section: Methodsmentioning

confidence: 99%

Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation

Qiao,

Wu,

Chen

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.

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Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors

Cited by 8 publications

References 50 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2021

Fragment-to-Lead Medicinal Chemistry Publications in 2021

The SARS-CoV-2 spike S1 protein induces global proteomic changes in ATII-like rat L2 cells that are attenuated by hyaluronan

Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation

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