The MDS consistently demonstrated the formation of stable protein-ligand complexes between FGFR3 and Cycloartobiloxanthone/Desoxylimonin throughout the trajectory. Based on these results, it can be inferred that Cycloartobiloxanthone and Desoxylimonin can potentially serve as valuable scaffolds in developing drugs targeting FGFR3 for cancer therapeutic after required validation.

Collaboration between nephrologists and oncologists is crucial for optimizing treatment benefits and managing side effects. Further research is warranted to refine management strategies and to understand the clinical implications of hyperphosphatemia.

Patients who developed cataracts had longer median (range) duration of FGFRi treatment compared with patients who did not develop cataracts (13 months [2-26] vs 5 months [1-11]; odds ratio, 1.01; 95% CI, 1.00-1.02; P = .02). While this retrospective case series study cannot prove cause and effect conclusively due to the study design, study results highlight cataract formation or progression as a potential adverse effect of FGFRi therapy, supporting consideration of periodic eye examinations in patients who have received this treatment.

Molecular docking simulation of 9a in the binding pocket of FGFR-1 confirms its capability to achieve the characteristic interactions of the type II FGFR-1 inhibitors. Exploration of the ADME properties of 9a-p by SwissADME web tool proved their satisfactory physicochemical properties for the discovery of new anticancer hits.

Conventional chemotherapy with gemcitabine and cisplatin for 19 months resulted in progressive disease. Subsequently, a comprehensive genome profile revealed fibroblast growth factor receptor 2 rearrangement, and hence, pemigatinib administration was initiated...Subsequently, the patient underwent conversion surgery, resulting in successful radical resection of the tumor. The patient has been disease-free for 7 months.

"However, limited evidence has been presented to date for the efficacy of futibatinib in patients progressing under treatment with a non-covalent inhibitor. Between January 2021 and April 2023, 14 patients received futibatinib after treatment with the non-covalent FGFR inhibitors pemigatinib (10 patients) or derazantinib (4 patients). Futibatinib was manageable and active in patients with iCCA progressing under a previously non-covalent FGFR2 inhibitor. Randomized controlled trials are needed to determine the optimal therapeutic approach between an upfront treatment with a covalent inhibitor or a sequential strategy starting with a non-covalent inhibitor, followed by a covalent one if disease progresses due to acquired mutations that this could address."

To gain further insights into the conformational dynamics of Mundulone and the reference FGFR1 inhibitor, Lenvatinib, we conducted time-evolution analyses employing 200 ns molecular dynamics simulations (MDS) and essential dynamics...Overall, the findings indicate that Mundulone exhibits promising binding affinity, specific interactions, and favorable drug profiles, making it a promising lead candidate. Further experimental analysis will be necessary to confirm its effectiveness and safety profiles for therapeutic advancement in the cancer field.Communicated by Ramaswamy H. Sarma.

FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

For example, AZD4547 and BGJ398 are gradually entering the consumption cycle and are good options as combined treatments. Artificial intelligence and drug repositioning methods can help preselect suitable drug targets more successfully for future inhibition of carcinogenicity.

We have previously documented that vitamin D and its low-calcaemic analogues enhance the anticancer activity of drugs including a classic chemotherapeutic-dacarbazine-and an antiangiogenic VEGFRs inhibitor-cediranib. In this study, we explored the response of A375 and RPMI7951 melanoma lines to CPL304110 (CPL110), a novel selective inhibitor of fibroblast growth factor receptors (FGFRs), and compared its efficacy with that of AZD4547, the first-generation FGFRs selective inhibitor...Interestingly, 1,25(OH)2D3 and CPL304110 co-treatment resulted in activation of the ERK1/2 pathway in A375 cells. Our results strongly suggested possible crosstalk between vitamin D-activated pathways and activity of FGFR inhibitors, which should be considered in further clinical studies.

FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse.

Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

Comparative analyses with FDA-approved FGFR inhibitors, erdafitinib and pemigatinib, revealed certain advantages of CPL304110 in both in vitro and in vivo assessments. Encouraging preclinical results led the way for the initiation of a Phase I clinical trial (01FGFR2018; NCT04149691) to further evaluate CPL304110 as a novel anticancer therapy.

It is still possible to achieve durable tumor response in advanced previously treated intrahepatic cholangiocarcinoma through targeted therapies. The prolonged progression free survival means that there could be an increased risk of secondary malignancy in this patient group, which necessitates diagnostic and therapeutic strategies.

Cancer treatments using FGFRi are showing promising results but their ocular toxicity is not well reported nor fully understood. Oncologists should be aware of the potential risks associated with FGFRi and involve ophthalmologists for the follow-up of their patients. The toxicity of FGFRi seems to resolve after drug continuation, but a certain degree of infra clinical RPE impairment may persist. Longer term follow-ups are warranted to further understand the effects of FGFRi on the RPE.

The developed assay method was applied to a clinical trial of E7090, and plasma concentrations of E7090 and M2 were quantifiable up to 144 h postdose. These results indicated that the developed more sensitive assay was reproducible and was successfully applied to a clinical trial of E7090.

Similarities between toxicities observed from other targeted cancer therapy drugs and FGFR inhibitors may help us understand underlying pathophysiological changes. The management of these adverse events requires close ophthalmologic follow-up and may require discontinuation of the offending agents in some cases.

Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]).

Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

In conclusion, anti-FGF2 ds-Diabody could inhibit the expression of PD-L1 and EMT of hepatoma cells through FGF2/FGFR4/STAT3 axis. These results suggested that anti-FGF2 ds-Diabody has potential clinical application in inhibiting metastasis and immune escape of hepatocellular carcinoma.

The developed inhibitor prediction model (FGFR1Pred) provides a valuable tool for identifying potential FGFR1 inhibitors, expediting the drug discovery process and ultimately facilitating the development of new therapeutics. The model is made available at https://github.com/PGlab-NIPER/FGFR1Pred.git.

Herein, we discovered a series of novel quinolone-based covalent pan-FGFR inhibitors by further optimizing the lead compound (lenvatinib) under the guidance of molecular docking...The irreversible binding to target proteins was characterized by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Moreover, I-5 exhibited favorable PK properties in vivo and induced significant TGI in the Huh-7 and NCI-H1581 xenograft mouse models.

Identification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit. Early identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer.

Infigratinib, futibatinib, and pemigatinib are being evaluated in an open phase III trial versus gemcitabine/cisplatin as first line treatment for locally advanced or metastatic CCA with FGFR GA (PROOF-301 NCT03773302, FOENIX-CCA3 NCT04093362, FIGHT-302 NCT03656536). Unfortunately, the effectiveness of FGFR therapy is often limited by acquired resistance mechanisms and continued work is needed to understand and overcome these mechanisms of resistance.

The approval of this medicine was based on phase 3 clinical trial results including an overall response rate (ORR) of 42% and a duration of response (DoR) of 9.7 months. This short perspective summarizes Futibatinib's synthesis, physicochemical properties, dosage, route of administration, mechanism of action, binding mode, pharmacodynamics, pharmacokinetics, drug interactions, adverse events, and possible mechanism of resistance.

With C4 cut-off and prophylactic bile acid sequestrant implementation, INCB062079 demonstrated a manageable safety profile and evidence of target inhibition. In view of the rarity of FGF19/FGFR4 alterations and slow patient accrual, the study was terminated before establishing an MTD.

Preliminary data showed that BLU-554 in combination with CS1001 is safe and effective for treatment of patients with locally advanced or metastatic HCC.

The combination showed synergy (5) or additivity (2), and no antagonism, with synergy significantly associated (P < 0.05) with higher levels of M2-type macrophages. The association of strong efficacy of the combination in vivo with M2 macrophages, which are known to express CSF1R, and the absence of synergy in vitro is consistent with the tumor microenvironment also being a factor in DZB efficacy and suggests additional means by which DZB could be stratified for cancer treatment in the clinic.

Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable antiproliferative activity in FGFR-aberrant cancer cell lines. In addition, the oral administration of 2e in the FGFR1-amplified H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models demonstrated potent antitumor efficacy, inducing tumor stasis or even tumor regression.

Recently, immunotherapy and target therapy are gaining a foothold in the treatment of metastatic disease, with pembrolizumab and atezolizumab showing encouraging results in combination with chemotherapy as a first-line strategy. Regarding the target therapy, erdafitinib, a fibroblast growth factor receptor inhibitor, and enfortumab vedotin, an antibody-drug conjugate, proved to have a strong antitumor property, likely due to the distinctive immune-genetic background of UTUC. In this context, great efforts have been addressed to uncover the biological, immunological, and clinical grounds in UTUC patients in order to achieve a personalized treatment.

DZB inhibited growth of three tumor xenograft models with reported expression or amplification of CSF1R, whereas the specific FGFRi, pemigatinib, had no efficacy. Similar modulation of the tumor microenvironment was observed in an FGFR-insensitive syngeneic bladder model, MBT-2. These data confirm CSF1R as an important oncology target for DZB and provide mechanistic insight for the ongoing clinical trials, in which DZB is combined with the PD-L1 antibody, atezolizumab.

A clinical trial of nivolumab in an adjuvant setting (CheckMate 274) implied that immune-checkpoint inhibitors might be less efficacious in UTUC than in UBC...Clinical trials of enfortumab vedotin in a third-line setting (EV201 and EV301) implied that enfortumab vedotin might be less efficacious in UTUC than in UBC...Clinical differences in the effects of targeted drugs for UTUC and UBC may highlight the molecular differences between these diseases. The treatment strategy should be optimized based on further investigation of the molecular characteristics of UTUC.

Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study.

Accuracy and precision were measured during the reproducibility assessments and were within ± 7.0% and 9.1%, respectively, in plasma and within ± 7.0% and 5.8%, respectively, in urine, indicating sufficient reproducibility. The validated methods were successfully applied to the quantification of E7090 in human plasma and urine to support a Phase-1 clinical trial.

Futibatinib was approved in the USA on 30 September 2022 for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harbouring FGFR2 gene fusions or other rearrangements. This article summarizes the milestones in the development of futibatinib leading to this first approval.

The 18 responsive lines showed relatively high F/E (median, 16.4), whereas 29 nonresponsive lines had low F/E (median, 9.2) (P = 0.0006). These results suggest that F/E is another strong predictor of responses to FGFRi that is as useful as the current genomic criteria based solely on the FGFR genomic changes.

In addition, we found that ABSK011 increased CD8 + T cell infiltration in humanized HCC mouse models. Conclusions These preclinical data demonstrated that ABSK011 treatment increased IFN related response as well as CD8 + T cell infiltration in FGF19 overexpressed HCC models, supporting the combination of FGFR4 inhibitor and immune checkpoint molecules such as anti-PD-(L)1 antibodies to achieve enhanced antitumor activity.

Moreover, biPSCs and bESCs labeled with GFP were able to contribute to chimeric blastocysts. Additionally, biPSCs have shown promising potential for contributing to chimeric blastocysts and for future studies.

This signaling pathway also attenuated the expression of c-Jun and c-Fos. The findings implicate TTYH3 as a potential factor regulating the properties of bladder cancer and as a therapeutic target.

In conclusion, sulfatinib and SPP86 displayed a relevant antitumor activity both in vitro and in vivo. Moreover, this work suggests the potential utility of targeting FGFR and VEGFR signaling pathways as an alternative therapy for MTC.