A Phase 1, Open Label, Dose Escalation Study Evaluating the Safety and Pharmacokinetics of Enteric Coated D-3263 Hydrochloride in Subjects With Advanced Solid Tumors

This is a Phase 1, dose escalation study evaluating safety and pharmacokinetics of enteric coated D-3263 HCl in subjects with advanced solid tumors

Start Date01 Mar 2009

Sponsor / Collaborator

Dendreon Corp.

100 Clinical Results associated with D-3263

100 Translational Medicine associated with D-3263

100 Patents (Medical) associated with D-3263

Literatures (Medical) associated with D-3263

01 Nov 2024·LUTS: Lower Urinary Tract Symptoms

Transient Receptor Potential Melastatin 8 Contributes to Cystitis‐Induced Neuronal Sprouting and Pain Hypersensitivity Through AKT/mTOR Signaling Pathway in Interstitial Cystitis/Bladder Pain Syndrome

Article

Author: Zhang, Peng ; Chang, Ran ; Wu, Liyang

ABSTRACTObjectivesThe aim of this study was to investigate the mechanism of TRPM8 in neuroproliferation and pain, as well as the relevance of the Akt/mTOR signaling pathway in mice with IC/BPS.MethodsThe model of IC/BPS was established in wild and TRPM8−/− mice. The mechanical sensitivity was measured. The number of neurite segments, length of neurites, and density of neurites were all counted. IL‐6 and norepinephrine levels were detected by ELISA, Western blot was used to detect protein levels of TRPM8, Akt, p‐Akt, mTOR, p‐mTOR. Immunofluorescence was used to detect TRPM8 expression and distribution in neurites, neurons, and sensory nerves in mouse bladder tissue.ResultsPain threshold in the IC/BPS group was decreased, and neurite segments, length, and density were all significantly enhanced when compared to the control group. The parameters in the IC/BPS model + Menthol group were more statistically significant. Neurite number and density were lower in TRPM8 knockout‐model mice than in IC/BPS model mice. The expression of TRPM8 and the ratios of p‐Akt/Akt and p‐mTOR/mTOR rose in the IC/BPS model group. In TRPM8 knockout‐model mice, the ratios of p‐Akt/Akt and p‐mTOR/mTOR were not substantially different from those in the control group. TRPM8 knockout‐model mice had considerably lower levels of serum IL‐6 and urine norepinephrine than IC/BPS model mice.ConclusionsTRPM8 can induce pain hypersensitivity and sensory nerve proliferation by activating Akt/mTOR pathway and raising the expression of IL‐6 and norepinephrine in IC/BPS models. These findings offer new perspectives on IC/BPS treatment.

BMC Microbiology

Antibacterial activity and mechanisms of D-3263 against Staphylococcus aureus

Article

Author: Liu, Xiaoju ; Wen, Zewen ; Cai, Shuyu ; Deng, Qiwen ; Chen, Zhong ; Peng, Renhai ; Yu, Zhijian ; Zhang, Yufang ; Hou, Tieying ; Xiong, Yanpeng

AbstractMulti-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8) agonist, has potential antineoplastic properties. Here, we reported the antibacterial and antibiofilm activities of D-3263. Minimum inhibitory concentrations (MICs) against S. aureus, Enterococcus faecalis and E. faecium were ≤ 50 µM. D-3263 exhibited bactericidal effects against clinical methicillin-resistant S. aureus (MRSA) and E. faecalis strains at 4× MIC. Subinhibitory D-3263 concentrations effectively inhibited S. aureus and E. faecalis biofilms, with higher concentrations also clearing mature biofilms. Proteomic analysis revealed differential expression of 29 proteins under 1/2 × MIC D-3263, influencing amino acid biosynthesis and carbohydrate metabolism. Additionally, D-3263 enhanced membrane permeability of S. aureus and E. faecalis. Bacterial membrane phospholipids phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) dose-dependently increased D-3263 MICs. Overall, our data suggested that D-3263 exhibited potent antibacterial and antibiofilm activities against S. aureus by targeting the cell membrane.

BiomoleculesQ3 · BIOLOGY

Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies

Q3 · BIOLOGY

ArticleOA

Author: Alaimo, Alessandro ; Barbareschi, Mattia ; Montironi, Rodolfo ; Vignoli, Beatrice ; Canossa, Marco ; Moro, Riccardo ; Carbone, Francesco Giuseppe ; Genovesi, Sacha ; Lunardi, Andrea ; De Felice, Dario

Metastatic prostate cancer (mPCa) is one of the leading causes of cancer-related mortality in both the US and Europe. Androgen deprivation is the first-line therapy for mPCa; however, resistance to therapy inevitably occurs and the disease progresses to the castration resistant stage, which is uncurable. A definition of novel targeted therapies is necessary for the establishment of innovative and more effective protocols of personalized oncology. We employed genetically engineered mouse models of PCa and human samples to characterize the expression of the TRPM8 cation channel in both hormone naïve and castration resistant tumors. We show that Trpm8 expression marks both indolent (Pten-null) and aggressive (Pten/Trp53 double-null and TRAMP) mouse prostate adenocarcinomas. Importantly, both mouse and human castration-resistant PCa preserve TRPM8 protein expression. Finally, we tested the effect of TRPM8 agonist D-3263 administration in combination with enzalutamide or docetaxel on the viability of aggressive mouse PCa cell lines. Our data demonstrate that D-3263 substantially enhances the pro-apoptotic activity of enzalutamide and docetaxel in TRAMP-C1 e TRAMP-C2 PCa cell lines. To conclude, this study provides the basis for pre-clinical in vivo testing of TRPM8 targeting as a novel strategy to implement the efficacy of standard-of-care treatments for advanced PCa.

100 Deals associated with D-3263

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	US	Dendreon Corp.	01 Mar 2009
Prostatic Hyperplasia	Phase 1	-	Dendreon Corp.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ACR2013	Not Applicable	Endothelial dysfunction	-	TRPM8 (SSc MVEC)	htlnfhvyex(vkxfpfqswm) = dmugkgxojc hlhveltvcv (vypimpjkfx ) View more	-	25 Oct 2013
SFN2009	Not Applicable	Cutaneous hypersensitivity	-	TRPM8 receptor (TRPM8+ cells)	jjotuvnaxk(xtkcnjzdje) = vigcrogift lyuhwttbds (yqbbknvais )	-	21 Oct 2009
SFN2009	Not Applicable	Cutaneous hypersensitivity	-	TRPM8 receptor (TRPM8- cells)	jjotuvnaxk(xtkcnjzdje) = txzpsklduo lyuhwttbds (yqbbknvais )	-	21 Oct 2009

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