Development of the phenylpyrazolo[3,4-<i>d</i>]pyrimidine-based, insulin-like growth factor receptor/Src/AXL-targeting small molecule kinase inhibitor

Lee, Ho Jin; Pham, Phuong Chi T.; Pei, Honglan; Lim, Bumhee; Hyun, Sangwon; Baek, Byungyeob; Kim, Byungjin; Kim, Yunha; Kim, Min Hwan; Kang, Nae Won; Min, Hye Young; Kim, Dae Duk; Lee, Jeeyeon

doi:10.7150/thno.48865

Cited by 12 publications

(10 citation statements)

References 83 publications

(61 reference statements)

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“…Since chemotherapeutic drugs and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) were found to promote immune escape of NSCLC cells by upregulating PD-L1 expression 54 , 55 , we hypothesized that NCT-80-mediated Hsp90 blockade may enhance antitumor activities of chemotherapy and EGFR-targeting anticancer therapy. Indeed, H460/PcR, H1299/CsR, H1299/PmR, and PC9/ER 25 - 27 cells displayed upregulated PD-L1 expression ( Figure 6 C ), and treatment with NCT-80 considerably suppressed PD-L1 expression and induced PARP cleavage ( Figure 6 D ). More importantly, combinatorial treatment with NCT-80 and chemotherapeutic agents (paclitaxel and cisplatin in combination, Pc/Cs) more effectively suppressed the growth of LLC-Luc allograft tumors ( Figure 6 E ).…”

Section: Resultsmentioning

confidence: 98%

“…NCT-80 significantly inhibited NSCLC cell viability ( Figure 5 A ) and colony formation under anchorage-dependent ( Figure 5 B ) and anchorage-independent ( Figure 5 C ) culture conditions in a dose-dependent manner. Considering the clinical utility of anticancer therapy for patients who progressed upon chemotherapy and molecular targeted therapy and recent studies showing Hsp90 involvement in the resistance to various antitumor agents including chemotherapy and molecular targeted therapy 48 , we additionally evaluated the effect of NCT-80 on the viability and colony-forming capacities of several NSCLC cell sublines that are resistant to chemotherapeutics (designated '/R'), including paclitaxel (H460/PcR), cisplatin (H1299/CsR), and pemetrexed (H1299/PmR), and the EGFR TKI erlotinib (PC9/ER), which were established in our previous studies 25 - 27 . NCT-80 exhibited comparable inhibitory effects on the viability ( Figure 5 D ) and colony-forming capacities ( Figure 5 E ) of these drug resistant cells.…”

Section: Resultsmentioning

confidence: 99%

“…Sang Kook Lee (Seoul National University). Drug resistant H1299/CsR, H1299/PmR, H460/PcR, and PC9/ER cells were generated by continuous exposure to increasing concentrations of cisplatin (H1299/CsR), pemetrexed (H1299/PmR), paclitaxel (H460/R), or erlotinib (PC9/ER) for more than six months 25 - 27 . The NSCLC cell lines were authenticated and validated in 2013 at the Korean Cell Line Bank using an AmplFLSTR Identifier PCR Amplification Kit (Applied Biosystems, Foster, CA, USA; cat.…”

Section: Methodsmentioning

confidence: 99%

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A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects

Lee¹,

Min²,

Yong³

et al. 2022

Theranostics

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Rationale: The heat shock protein (Hsp) system plays important roles in cancer stem cell (CSC) and non-CSC populations. However, limited efficacy due to drug resistance and toxicity are obstacles to clinical use of Hsp90 inhibitors, suggesting the necessity to develop novel Hsp90 inhibitors overcoming these limitations. Methods: The underlying mechanism of resistance to Hsp90 inhibitors was investigated by colony formation assay, sphere formation assay, western blot analysis, and real-time PCR. To develop anticancer Hsp90 inhibitors that overcome the signal transducer and activator of transcription 3 (STAT3)-mediated resistance, we synthesized and screened a series of synthetic deguelin-based compounds in terms of inhibition of colony formation, migration, and viability of non-small cell lung cancer (NSCLC) cells and toxicity to normal cells. Regulation of Hsp90 by the selected compound NCT-80 [5-methoxy-N-(3-methoxy-4-(2-(pyridin-3-yl)ethoxy)phenyl)-2,2-dimethyl-2H-chromene-6-carboxamide] was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. The antitumor, antimetastatic, and anti-CSC effects of NCT-80 were examined in vitro and in vivo using various assays such as MTT, colony formation, and migration assays and flow cytometric analysis and tumor xenograft models. Results: We demonstrated a distinct mechanism in which Hsp90 inhibitors that block N-terminal ATP-binding pocket causes transcriptional upregulation of Wnt ligands through Akt- and ERK-mediated activation of STAT3, resulting in NSCLC cell survival in an autocrine or paracrine manner. In addition, NCT-80 effectively reduced viability, colony formation, migration, and CSC-like phenotypes of NSCLC cells and their sublines with acquired resistance to anticancer drugs by inducing apoptosis and inhibiting epithelial-mesenchymal transition and the growth of NSCLC patient-derived xenograft tumors without overt toxicity. With regards to mechanism, NCT-80 directly bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the interaction between Hsp90 and STAT3 and degrading STAT3 protein. Moreover, NCT-80 inhibited chemotherapy- and EGFR TKI-induced programmed cell death ligand 1 expression and potentiated the antitumor effect of chemotherapy in the LLC-Luc allograft model. Conclusions: These data indicate the potential of STAT3/Wnt signaling pathway as a target to overcome resistance to Hsp90 inhibitors and NCT-80 as a novel Hsp90 inhibitor that targets both CSCs and non-CSCs in NSCLC.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects

Lee¹,

Min²,

Yong³

et al. 2022

Theranostics

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“…Hence, the development of novel multitarget inhibitors that block IGF1Rs is immediately indispensable. One of the most potent IGF-1R inhibitors, phenylpyrazolo[3,4- d ]pyrimidine, showed fabulous antitumor activities in the NSCLC induced xenograft and allograft model [ 97 ]. Gadekar and colleagues proposed 2,3-dihydroimidazo[2,1- b ]thiazoles as dual EGFR and IGF1R inhibitors with reasonable drug likeness properties [ 98 ].…”

Section: Recent Updates On Selective Tyrosine Kinase Inhibitors In Pre-clinical Studiesmentioning

confidence: 99%

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Mongre

Mishra

Shukla

et al. 2021

IJMS

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GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.

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“…Additionally, increased IGF-1R signaling was observed in AXL-low mt EGFR -expressing NSCLC tumor cells treated with osimertinib and knockout of IGF-1R sensitized AXL-low NSCLC cells to osimertinib, suggesting that IGF-1R drives cell survival in the presence of osimertinib [ 241 ]. Indeed, transient IGF-1R inhibition combined with continuous osimertinib eradicated tumors and provided durable tumor growth inhibition even after cessation of osimertinib [ 241 , 243 ].…”

Section: Targeting Tam Kinases and Egfr In Nsclcmentioning

confidence: 99%

Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

Yan

Earp

DeRyckere

et al. 2021

Cancers

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MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations.

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Development of the phenylpyrazolo[3,4-d]pyrimidine-based, insulin-like growth factor receptor/Src/AXL-targeting small molecule kinase inhibitor

Cited by 12 publications

References 83 publications

A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects

A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

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