dovitinib (TKI258)

Then we detected 10 repurposable drug molecules (Irinotecan, Imatinib, Telaglenastat, Olaparib, RG-4733, Sorafenib, Sitravatinib, Cabozantinib, Abemaciclib, and Dovitinib.) by molecular docking with KGs-mediated receptor proteins. Their ADME/T analysis and cross-validation with the independent receptors, also supported their potent against ccRCC. Therefore, these outputs might be useful inputs/resources to the wet-lab researchers and clinicians for considering an effective treatment strategy against ccRCC.

Finally, sKGs-guided top-ranked three repurposable drug molecules (Digoxin, Imatinib, and Dovitinib) were recommended as the common treatment for both T2D and ccRCC by molecular docking and ADME/T analysis. Therefore, the results of this study may be useful for diagnosis and therapies of ccRCC patients who are also suffering from T2D.

Next, we explored the latest FLT3-targeting PROTACs developed in the past few years such as quizartinib-based PROTACs, dovitinib-based PROTACs, gilteritinib-based PROTACs, and others. Then, we followed with a deep analysis of their advantages regarding potency improvement and overcoming AML drug resistance. Finally, we discussed the challenges facing these chimeric molecules with proposed future solutions to circumvent them.

Current clinical trials, including those evaluating FGFR inhibitors like erdafitinib, lucitanib, and dovitinib, have demonstrated mixed outcomes, underscoring the complexity of FGFR signaling in breast cancer. In conclusion, targeting FGFR signaling in ER+ breast cancer presents both challenges and opportunities. A deeper understanding of the molecular mechanisms and resistance pathways is crucial for the successful integration of FGFR inhibitors into clinical practice, aiming to improve outcomes for patients with endocrine-resistant breast cancer.

Also, PharmacoGx data indicated that the expression level of SDHB was correlated with drug sensitivity to Crizotinib and Dovitinib. Our findings highlight the potential association between alterations in the expression of genes such as HOXC6, HOXC13, HOXC8, TBX15, SDHB, COX5A, and UQCRC1 and increased mortality rates in CRC patients. As revealed by the PPI network, these genes exhibited the most connections with other genes linked to survival.

Ligand-based virtual screening and molecular docking were performed, resulting in the selection of three lead compounds (CID_135698391, CID_135453100, CID_136599608) with superior binding affinities compared to the reference compound dovitinib...Overall, small-molecule compounds CID_135453100 and CID_136599608 showed promising binding interactions and stability, suggesting their potential as direct inhibitors of STK17B. These findings could contribute to the exploration of novel therapeutic options targeting STK17B in cancer treatment.Communicated by Ramaswamy H. Sarma.

Bortezomib and Axitinib exhibited high efficacy on the patient's sample...Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2: : FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor)... Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2: : FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2: : FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the treatment of patients with FGFR1-fusion positive leukemias.

In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects.

Based on the gene module, polyethylene glycol, gallic acid, pyrazole, cordycepin, phenothiazine, pantoprazole, cysteamine, indisulam, valinomycin, trametinib, BRD-K81473043, AZD8055, dovitinib, BRD-A17065207, and tyrphostin AG1478 presented as drugs and small molecule candidates previously studied in the CRC. Lornoxicam, suxamethonium, oprelvekin, sirukumab, levetiracetam, sulpiride, NVP-TAE684, AS605240, 480743.cdx, HDAC6 inhibitor ISOX, BRD-K03829970, and L-6307 are proposed as novel drugs and small molecule candidates for CRC.

Visual inspection and binding energy analysis revealed that the compounds OSU-03012, Raltitrexed, Ostarine (MK-2866), Dovitinib (TKI-258), and Varespladib (LY315920) had strong binding affinity for the MCL-1 protein. These findings suggest that these compounds may be useful as MCL-1 inhibitors in the treatment of breast cancer. However, additional experimental validation is required to confirm these findings.

Herein, we used a tetracycline (Tet)-inducible RNAi-mediated expression silencing cell system to investigate how UBR5 enables postsurgical mammary tumor metastatic growth in mouse lungs without the continuous influence of the primary lesion...Moreover, doxycycline-induced UBR5 expression knockdown in metastatic cells in the lungs, following removing the primary tumors, resulted in increased apoptosis, decreased proliferation and prolonged survival, whereas silencing the expression of cell division cycle 73 (CDC73), a tumor suppressor and E3 ligase substrate of UBR5, reversed these effects. Transcriptome analyses revealed a prominent role of the p53 pathway in dovitinib-induced apoptosis of tumor cells differentially regulated by UBR5 and CDC73...Furthermore, a xenograft model of human TNBC recapitulated the metastatic properties and characteristics of the unique UBR5-CDC73 functional antagonism. This study reveals the novel and critical roles and intricate relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and indicates the potential of targeting this pathway in cancer therapy.

"Allarity Therapeutics, Inc...is pleased to announce that the Company has been invited to give a presentation at Biomarkers Europe 2023. The presentation will focus on Allarity’s development of drug-specific DRP^® companion diagnostics (CDx) for oncology therapeutics, featuring clinical validation for several exemplary DRP^® CDx....In addition to its presentation, Allarity is honored to participate in a panel discussion titled 'Prediction Of Drug Response Using An Ex Vivo Organ Culture (EVOC) On Oncology Patients, Clinical Trial Development And Patient Testing' at the same conference."

The DRP-Dovitinib shows promise as a potential biomarker for identifying advanced RCC patients most likely to experience clinical benefit from dovitinib treatment, subject to confirmation in an independent prospective trial of dovitinib in RCC patients.

P=NA | N=135 | "Allarity Therapeutics...announced today the publication of its clinical validation of a novel drug-specific DRP®-companion diagnostic (CDx) for dovitinib in the peer-reviewed journal PLOS ONE. Data showed that the DRP®-Dovitinib CDx was able to identify a subgroup of advanced renal cell carcinoma (RCC) patients that have improved clinical benefit from treatment with dovitinib, as compared to unselected patients....In the study evaluating pre-treatment biopsies of 135 advanced RCC patients, the DRP® positive subgroup (indicating that the patient was likely to respond) (N=49) had a median overall survival of 15 months (96% CI 12.94-26.25), whereas the DRP® negative subgroup (N=86) had a median overall survival of 9.13 months (95% CI 7.49-13.2)."

Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells.

For patients of IMDDR subtype, we recommend the combination of venetoclax and PHA-665752. A-674563 and dovitinib could be combined with DDR inhibitors to treat patients in IMDDR subtype. Moreover, single-cell analysis revealed that there are more immune cells clustered in the IMDDR subtype and higher number of monocyte-like cells, which exert immunosuppressive effects, in the IMDDR subtype. These findings can be applied for molecular stratification of patients and might contribute to the development of personalized targeted therapies for AML.

Tumoroids werethen treated with stromal targeting strategies for TGF-beta (galunisertib), the FGF pathway(Dovitinib), FAK inhibitors (defactinib), and cell adhesion modulators (plerixafor) alone or incombination with nivolumab for 72-hours ex vivo. Treatment-mediated changes in the tumor immune microenvironment was furthercorroborated by a multiplex cytokine release assay detecting GM-CSF, sCD137, IFNγ, sFas,sFasL, Granzyme A, Granzyme B, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, MIP-1α, MIP-1β, TNF-α,Perforin in tumoroid culture media and correlated with clinicopathologic findings and PD-L1expression for individual tumnors. Further, this 3D-tumoroid platform provides unique insightinto the microenvironment of both treatment responsive and non-responsive tumors and can aidin the development of patient-centered therapeutic regimens.

We selected 3 NET organoids (NET16, NET17 and NET18) to test the activity of select drugs: dovitinib (VEGFR inhibitor), vistusertib (mTOR inhibitor), cobimetinib (mitogen-activated protein kinase 1 inhibitor) and TAK243 (ubiquitin activating enzyme inhibitor). Tumor heterogeneity may be contributing to the differences seen in the drug response between the three NET organoids and requires further evaluation. Replication of these studies in a larger subset of patient samples and drug combination studies will be important for the advancement of therapeutics in NETs.

Conversion of Dovitinib into this RiboTAC reprograms the known drug to selectively affect the RNA target. This work demonstrates that DEL can be used to identify compounds that bind and recruit proteins with effector functions in heterobifunctional compounds.

The present preclinical study evaluated the potential use of the fibroblast growth factor receptor inhibitors infigratinib and dovitinib alone or in combination with the mitogen-activated protein kinase inhibitor binimetinib in mouse models of GIST with different sensitivity or resistance to imatinib. In a model with KIT exon 11 and 17 mutations, dovitinib induced tumor necrosis, most likely due to anti-angiogenic effects. Additive effects combining dovitinib with binimetinib were limited.

"Following several weeks of analysis by Company leadership together with clinical and regulatory experts, Allarity has now filed a formal request with the FDA for a 'Type C' meeting to further discuss potential clinical paths to support approval of dovitinib, together with its DRP^®-Dovitinib companion diagnostic, in view of the FDA’s recent RTFs....The Company anticipates providing a further update on the outcome of its FDA meeting and the future of the dovitinib program before the end of the third quarter of this year."

BLISS analysis of dual treatment with EGFR TKI neratinib and dasatinib or dovitinib revealed synergistic drug interactions in most lines...Acute response was examined by treating drug-naïve cells with afatinib over 48h, and long-term kinome rewiring was observed by comparing untreated cells to gefitinib- and erlotinib-resistant cell lines...Eight of these kinases (Cdk19, Ddr1, Kalrn, Khk, Mapk3, Pink1, Tnik, Ulk2) appear in both the in vitro and in vivo datasets, indicating a conserved kinome response regardless of method of resistance generation. Overall, integrated kinome profiling in GBM models with defined mutational profiles provides a powerful framework to identify novel therapeutic targets that could significantly alter current treatment paradigms.

"Allarity Therapeutics...announced that the...FDA has provided the Company with Refusal to File ('RTF') letters regarding the new drug application ('NDA') for dovitinib, and its accompanying pre-market approval ('PMA') application for the DRP®-Dovitinib companion diagnostic, for the third-line treatment of metastatic renal cell carcinoma ('mRCC'). Upon preliminary review, the FDA determined that the NDA, submitted on December 22, 2021, and the PMA application, submitted on April 2, 2021, were not sufficiently complete to permit substantive reviews....Allarity intends to seek guidance from the FDA on how to further advance dovitinib and its accompanying DRP®-Dovitinib companion diagnostic towards approval."

Immunoblot analyses of MKN-45 and KATO-III cells revealed that dovitinib decreased phospho-FGFR, phospho-AKT, phospho-ERK, phospho-p70S6K, phospho-4EBP1, Bcl-2 and increased cleaved PARP-1, cleaved-caspase-3, p27, Bax, Bim, with an additive effect from combination therapy. These results demonstrate that the FGFR/VEGFR/PDGFR inhibitor, dovitinib, has the potential to augment the antitumor effects of nab-paclitaxel, with implications for use in the advancement of clinical GAC therapy.

"Allarity Therapeutics, Inc...and Oncoheroes Biosciences, Inc...announced that they have entered into licensing agreements under which Oncoheroes will acquire exclusive, global development rights to Allarity’s therapeutic candidates dovitinib, a pan-targeted kinase inhibitor (pan-TKI), and stenoparib, a PARP inhibitor, and assume responsibility for their further clinical development in pediatric cancers...Under the terms of the licensing agreements, Oncoheroes acquires global, exclusive rights to fund and conduct further clinical development of both dovitinib and stenoparib in pediatric cancers...Allarity will support Oncoheroes’ pediatric clinical trials by providing clinical-grade drug inventory at cost and by facilitating DRP® companion diagnostic screening of pediatric patients for each drug...the Company is also planning a clinical trial of dovitnib in pediatric patients with osteosarcoma, in partnership with Oncoheroes..."

"Allarity Therapeutics, Inc...announced the submission of a new drug application (NDA) with the U.S. Food and Drug Administration (FDA) seeking marketing approval for dovitinib for the third-line treatment of renal cell carcinoma (RCC) patients....The Company’s NDA filing is supported by its prior PMA submission with the FDA for use of Dovitinib-DRP^®, the Company’s validated companion diagnostic for the drug, to select and treat RCC patients most likely to respond to dovitinib."

Cell-based screening of FGFR inhibitors with potential for clinical repurposing (NVP-BGJ398, nintedanib, dovitinib and ponatinib) revealed greater sensitivity of fusion-gene-positive versus -negative rhabdomyosarcoma cell lines and was shown to be correlated with high expression of FGFR2 and its specific ligand, FGF7. FGFR inhibition with NVP-BGJ398 reduced viability and was synergistic with SN-38, the active metabolite of irinotecan. In vivo, NVP-BGJ398 abrogated xenograft growth and warrants further investigation in combination with irinotecan as a therapeutic strategy for fusion-gene-positive rhabdomyosarcomas.

In 11 studies reporting on the response to FGFR inhibitors, complete response rates, disease control rates, and overall response rate of 0%-8%, 59.3%-64.2%, and 40% were reported for dovitinib, infigratinib, and erdafitinib, respectively. FGFR inhibitors have measurable benefit in patients with advanced and metastatic urothelial carcinoma. However, the results of ongoing RCTs and future well-designed studies are awaited to capture the differential biologic and clinical behavior of tumors harbouring FGFR while helping to identify those who are most likely to benefit from FGFR inhibitors.

As demonstrated from further biological evaluation, the compounds could induce the degradation of the FLT3-ITD and KIT proteins in a ubiquitin-proteasome-dependent manner and completely block their downstream signaling pathway. The findings of this study would provide another promising strategy to develop novel therapies for FLT3-ITD AML.

In the present study, we investigated anticancer mechanisms in the KM12SM cell line using three different form of dovitinib (dovitinib (free base), dovitinib lactate (mono acid), and dovitinib dilactic acid (diacid)) and four TRK inhibitors (LOXO-101, entrectinib, regorafenib, and crizotinib). These drugs significantly reduced expression of the phosphorylated proteins NFκB and COX-2 in the KM12SM cell line, and significantly attenuated KM12SM cell migration, according to a Transwell migration assay. Together, these results suggest that TRK inhibitors block products of carcinogenesis by negatively regulating the NFκB signaling pathway and positively regulating the antioxidant NRF2 signaling pathway.

In summary, calcitriol synergized dovitinib anticancer effects in vitro and in vivo, allowing for a significant dose-reduction of dovitinib while maintaining its antiproliferative potency. Our results suggest the beneficial convergence of independent antitumor mechanisms of dovitinib and calcitriol to inhibit TNBC-tumor growth.

By studying the binding interactions between RNA folds and known small-molecule medicines and mining the resultant dataset across human RNAs, we identified that Dovitinib, a receptor tyrosine kinase (RTK) inhibitor, binds the precursor to microRNA-21 (pre-miR-21)...By enhancing the inherent RNA-targeting activity and decreasing potency against canonical RTK protein targets in cells, the chimera shifted selectivity for pre-miR-21 by 2500-fold, alleviating disease progression in mouse models of triple-negative breast cancer and Alport Syndrome, both caused by miR-21 overexpression. Thus, targeted degradation can dramatically improve selectivity even across different biomolecules, i.e., protein versus RNA.

The DRP-Dovitinib can be used as a predictive biomarker and thus as a tool for the physician in identifying advanced RCC patients most likely to experiencing clinical benefit from dovitinib treatment.

Orthotopic liver transplantation may cure early and intermediate stage hepatocellular carcinoma. Considering the expected waiting time >6 months due to donor liver scarcity, there is an unmet need for effective neoadjuvant downsizing strategies. Angiogenesis inhibition by dovitinib does not negatively affect subsequent invasive procedures, is safe to administer immediately before locoregional therapy and may provide a novel treatment approach to improve patient outcomes if tolerability in HCC patients can be improved by therapeutic drug monitoring and personalized dosing.

FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS.

Pathway/process Genes FGF SEL1L3 LSM4 STAT6 - GATA3 VEGF VEGFA FABP5 DPP4 LDLR TMSB10 P4HA1 STAT6 RPL38 - HRAS UCP2 ATM GATA3 SPDEF CUL3 PDGF STAT6 UCP2 - TUG1 ATM GATA3 PI3K/Akt/mTOR REDD1 TRIM22 FABP5 MCT4 INSIG1 - HRAS SCAMP3 IGFBP5 ATM SRM CUL3 Drug resistance ABCF1 IGFBP5 Metastasis and hypoxia DPP4 REDD1 - ATM NDUFV1 CERS 2 CKB Topoisomerase HRAS APITD1 Other RPS20 TPK1 MIR196B HSPE1 CAV2 APOL1 PTPRE DPYSL2 ANP32B RPL27A EPB41L2 RPL3 - BAG5 BAG6 MARCH6 EMC3 CLPTM1 MAGEA1 LDOC1 ZNF331 TOB1 NDUFV1 MCUR1 NBPF10 PPP1R11 Pi3K/Akt/mTOR is downstream of FLT3, c-KIT and PDGFRA Conclusion The DRP-Dovitinib biomarker confirms many of the pathways known to be targeted by dovitinib, but also proposes novel mechanisms of resistance, such as ABC transporter F1. The DRP-Dovitinib is currently being employed in retrospective and prospective clinical trials with dovitinib.

Pathway/process Genes FGF SEL1L3 LSM4 STAT6 - GATA3 VEGF VEGFA FABP5 DPP4 LDLR TMSB10 P4HA1 STAT6 RPL38 - HRAS UCP2 ATM GATA3 SPDEF CUL3 PDGF STAT6 UCP2 - TUG1 ATM GATA3 PI3K/Akt/mTOR REDD1 TRIM22 FABP5 MCT4 INSIG1 - HRAS SCAMP3 IGFBP5 ATM SRM CUL3 Drug resistance ABCF1 IGFBP5 Metastasis and hypoxia DPP4 REDD1 - ATM NDUFV1 CERS 2 CKB Topoisomerase HRAS APITD1 Other RPS20 TPK1 MIR196B HSPE1 CAV2 APOL1 PTPRE DPYSL2 ANP32B RPL27A EPB41L2 RPL3 - BAG5 BAG6 MARCH6 EMC3 CLPTM1 MAGEA1 LDOC1 ZNF331 TOB1 NDUFV1 MCUR1 NBPF10 PPP1R11 Pi3K/Akt/mTOR is downstream of FLT3, c-KIT and PDGFRA Conclusion The DRP-Dovitinib biomarker confirms many of the pathways known to be targeted by dovitinib, but also proposes novel mechanisms of resistance, such as ABC transporter F1. The DRP-Dovitinib is currently being employed in retrospective and prospective clinical trials with dovitinib.

Pathway/process Genes FGF SEL1L3 LSM4 STAT6 - GATA3 VEGF VEGFA FABP5 DPP4 LDLR TMSB10 P4HA1 STAT6 RPL38 - HRAS UCP2 ATM GATA3 SPDEF CUL3 PDGF STAT6 UCP2 - TUG1 ATM GATA3 PI3K/Akt/mTOR REDD1 TRIM22 FABP5 MCT4 INSIG1 - HRAS SCAMP3 IGFBP5 ATM SRM CUL3 Drug resistance ABCF1 IGFBP5 Metastasis and hypoxia DPP4 REDD1 - ATM NDUFV1 CERS 2 CKB Topoisomerase HRAS APITD1 Other RPS20 TPK1 MIR196B HSPE1 CAV2 APOL1 PTPRE DPYSL2 ANP32B RPL27A EPB41L2 RPL3 - BAG5 BAG6 MARCH6 EMC3 CLPTM1 MAGEA1 LDOC1 ZNF331 TOB1 NDUFV1 MCUR1 NBPF10 PPP1R11 Pi3K/Akt/mTOR is downstream of FLT3, c-KIT and PDGFRA Conclusion The DRP-Dovitinib biomarker confirms many of the pathways known to be targeted by dovitinib, but also proposes novel mechanisms of resistance, such as ABC transporter F1. The DRP-Dovitinib is currently being employed in retrospective and prospective clinical trials with dovitinib.

Pathway/process Genes FGF SEL1L3 LSM4 STAT6 - GATA3 VEGF VEGFA FABP5 DPP4 LDLR TMSB10 P4HA1 STAT6 RPL38 - HRAS UCP2 ATM GATA3 SPDEF CUL3 PDGF STAT6 UCP2 - TUG1 ATM GATA3 PI3K/Akt/mTOR REDD1 TRIM22 FABP5 MCT4 INSIG1 - HRAS SCAMP3 IGFBP5 ATM SRM CUL3 Drug resistance ABCF1 IGFBP5 Metastasis and hypoxia DPP4 REDD1 - ATM NDUFV1 CERS 2 CKB Topoisomerase HRAS APITD1 Other RPS20 TPK1 MIR196B HSPE1 CAV2 APOL1 PTPRE DPYSL2 ANP32B RPL27A EPB41L2 RPL3 - BAG5 BAG6 MARCH6 EMC3 CLPTM1 MAGEA1 LDOC1 ZNF331 TOB1 NDUFV1 MCUR1 NBPF10 PPP1R11 Pi3K/Akt/mTOR is downstream of FLT3, c-KIT and PDGFRA Conclusion The DRP-Dovitinib biomarker confirms many of the pathways known to be targeted by dovitinib, but also proposes novel mechanisms of resistance, such as ABC transporter F1. The DRP-Dovitinib is currently being employed in retrospective and prospective clinical trials with dovitinib.

Small molecular compounds, such as A770041, Sorafenib, Nitedanib, and Dovitinib, relieve the autoinhibitory conformation. Activation of SHP-1 by M-dose CCRI ligands or the compounds described may prevent the progression of bone lesions in MM.