Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1–3)

Yamani, Abdellah; Zdżalik-Bielecka, Daria; Lipner, Joanna; Stańczak, Aleksandra; Piórkowska, Natalia; Stańczak, Paulina Seweryna; Olejkowska, Patrycja; Hucz-Kalitowska, Joanna; Magdycz, Marta; Dzwonek, Karolina; Dubiel, Krzysztof; Lamparska‐Przybysz, Monika; Popiel, Delfina; Pieczykolan, Jerzy; Wieczorek, Maciej

doi:10.1016/j.ejmech.2020.112990

Cited by 32 publications

(24 citation statements)

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“…Besides, compounds 312, 314, 316, 317 and 318 showed significant cytotoxicity against epidermal growth factor receptor tyrosine kinase with IC 50 values of 71.67–152.59 nM compared to IC 50 of standard erlotinib 152.59 nM. Finally, Yamani et al ( Yamani et al, 2021 ) applied scaffolds hybridization technique to formulate a total of 24 pyrazole-benzimidazole derivatives for blocking fibroblast growth factor receptors (FGFRs). Amongst the derivatives, compound 319 selectively inhibited FGFR (1–4) with IC 50 values of 0.75, 0.50, 3.05, and 87.90 nM, respectively.…”

Section: Biological Activitiesmentioning

confidence: 99%

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A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

et al. 2021

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Nowadays, nitrogenous heterocyclic molecules have attracted a great deal of interest among medicinal chemists. Among these potential heterocyclic drugs, benzimidazole scaffolds are considerably prevalent. Due to their isostructural pharmacophore of naturally occurring active biomolecules, benzimidazole derivatives have significant importance as chemotherapeutic agents in diverse clinical conditions. Researchers have synthesized plenty of benzimidazole derivatives in the last decades, amidst a large share of these compounds exerted excellent bioactivity against many ailments with outstanding bioavailability, safety, and stability profiles. In this comprehensive review, we have summarized the bioactivity of the benzimidazole derivatives reported in recent literature (2012–2021) with their available structure-activity relationship. Compounds bearing benzimidazole nucleus possess broad-spectrum pharmacological properties ranging from common antibacterial effects to the world’s most virulent diseases. Several promising therapeutic candidates are undergoing human trials, and some of these are going to be approved for clinical use. However, notable challenges, such as drug resistance, costly and tedious synthetic methods, little structural information of receptors, lack of advanced software, and so on, are still viable to be overcome for further research.

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Section: Biological Activitiesmentioning

confidence: 99%

“…Besides, compounds 312, 314, 316, 317 and 318 showed significant cytotoxicity against epidermal growth factor receptor tyrosine kinase with IC 50 values of 71.67-152.59 nM compared to IC 50 of standard erlotinib 152.59 nM. Finally, Yamani et al(Yamani et al, 2021) applied scaffolds hybridization technique to formulate a total of 24 pyrazole-…”

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confidence: 99%

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

et al. 2021

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“…CPL304110 is a selective, oral inhibitor of FGFR1-3. Preclinical data have showed a strong antiproliferative activity of this compound in a panel of human NSCLC cell lines harbouring FGFR aberrations and tumour growth inhibition in a gastric cancer FGFR2 -amplified mouse xenograft model [ 94 , 114 ]. CPL404110 inhibited cell proliferation with a higher potency than AZD4547 [ 114 ].…”

Section: Preclinical and Clinical Studies Of Fgfr Inhibitors In Lung Cancermentioning

confidence: 99%

“…CPL404110 inhibited cell proliferation with a higher potency than AZD4547 [ 114 ]. Given these promising results, CPL304110 has recently entered a phase I clinical trial (NCT04149691) to assess its safety, tolerability and pharmacokinetics in advanced solid malignancies, including SqCC with FGFR1-3 aberrations [ 94 ]. No results have been reported yet.…”

Section: Preclinical and Clinical Studies Of Fgfr Inhibitors In Lung Cancermentioning

confidence: 99%

Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer

Pacini

Jenks

Lima

et al. 2021

Cells

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Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. FGFR aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with FGFR alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target FGFR gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight our perspectives on the development of new biomarkers for stratification and prediction of FGFR inhibitor response to enable personalisation of treatment in patients with lung cancer.

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“…Since homozygous FGFR4 gene knockout causes no phenotypic loss of viability or fertility [ 224 ], this gene may have regulatory (tumor-suppressor) rather than mitogenic (oncogenic) properties [ 225 ]. For oncologic purposes, then, drugs inhibiting FGFRs 1–3 may be considered “pan”-FGFR inhibitors, and many inhibitors so defined—including TAS-120 [ 226 ], AZD4547, CPL304110 [ 227 ], BGJ398 (infigratinib) [ 228 ], and Debio 1347 [ 229 ]—have already been tested in trials [ 230 ]. The term “receptor nonselectivity” may therefore be better applied to drugs that cross-inhibit multiple receptor tyrosine kinases, such as VEGFR2, PDGFR β , CSF1R, FLT3, and KIT, and which include broad-spectrum partial FGFR antagonists such as dovitinib, ponatinib, and lenvatinib [ 38 ].…”

Section: Main Textmentioning

confidence: 99%

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology

Epstein

Liao²,

Gu³

2021

Journal of Oncology

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More than ten thousand peer-reviewed studies have assessed the role of fibroblast growth factors (FGFs) and their receptors (FGFRs) in cancer, but few patients have yet benefited from drugs targeting this molecular family. Strategizing how best to use FGFR-targeted drugs is complicated by multiple variables, including RNA splicing events that alter the affinity of ligands for FGFRs and hence change the outcomes of stromal-epithelial interactions. The effects of splicing are most relevant to FGFR2; expression of the FGFR2b splice isoform can restore apoptotic sensitivity to cancer cells, whereas switching to FGFR2c may drive tumor progression by triggering epithelial-mesenchymal transition. The differentiating and regulatory actions of wild-type FGFR2b contrast with the proliferative actions of FGFR1 and FGFR3, and may be converted to mitogenicity either by splice switching or by silencing of tumor suppressor genes such as CDH1 or PTEN. Exclusive use of small-molecule pan-FGFR inhibitors may thus cause nonselective blockade of FGFR2 isoforms with opposing actions, undermining the rationale of FGFR2 drug targeting. This splice-dependent ability of FGFR2 to switch between tumor-suppressing and -driving functions highlights an unmet oncologic need for isoform-specific drug targeting, e.g., by antibody inhibition of ligand-FGFR2c binding, as well as for more nuanced molecular pathology prediction of FGFR2 actions in different stromal-tumor contexts.

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Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1–3)

Cited by 32 publications

References 50 publications

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer

2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology

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