The purpose of this study is to evaluate the safety, tolerability, and MTD (maximum tolerated dose) of TTI-237 for the treatment of subjects with advanced malignant solid tumors.

Start Date01 Aug 2005

Sponsor / Collaborator

Wyeth AB

NCT00195247 / TerminatedPhase 1

A Phase 1 Dose Escalation Study of TTI-237 Administered Intravenously Every 3 Weeks in Subjects With Advanced Malignant Solid Tumors

The purpose of this study is to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of TTI-237 for the treatment of subjects with advanced malignant solid tumors.

Start Date01 May 2005

Sponsor / Collaborator

Wyeth AB

100 Clinical Results associated with Cevipabulin fumarate

100 Translational Medicine associated with Cevipabulin fumarate

100 Patents (Medical) associated with Cevipabulin fumarate

Literatures (Medical) associated with Cevipabulin fumarate

01 Jun 2024·Cytoskeleton

Cevipabulin induced abnormal tubulin protofilaments polymerization by binding to Vinblastine site and The Seventh site

Article

Author: Yang, Jianhong ; Bai, Peng ; Yan, Wei

AbstractMicrotubules, composed of αβ‐tubulin heterodimers, are crucial targets for chemotherapeutic agents and possess eight binding sites. Our previous study identified cevipabulin as the only one agent capable of simultaneously binding to two different sites (Vinblastine site and The Seventh site). Binding to The Seventh site by cevipabulin induces tubulin degradation. This study aimed to investigate whether it is binding to the Vinblastine site and The Seventh site exhibited an interactive cellular effect. Surprisingly, we discovered that cevipabulin induced abnormal tubulin protofilaments polymerization, a previously undefined tubulin morphology, and we proved it was an interactive effect of Cevipabulin's binding to both Vinblastine site and The Seventh site. Immunofluorescence and transmission electron microscopy confirmed cevipabulin induced the formation of linear tubulin protofilaments and their subsequent aggregation into irregular tubulin aggregates. Competition binding assays and the αY224G mutation revealed that binding of cevipabulin to both sites was necessary for the tubulin protofilaments polymerization effect. Moreover, we found that co‐treatment with a microtubule stabilization agent binding the Vinblastine site and a microtubule destabilization agent binding at the intra‐dimer interface of tubulin could also induce similar tubulin protofilaments polymerization. We proposed a mechanism where a microtubule stabilization agent on the Vinblastine site enhances longitudinal interactions between tubulin dimers, while, a microtubule destabilization agent binding at the intra‐dimer interface prevents the adoption of a straight conformation of the tubulin dimer and disrupts lateral interactions between tubulins, consequently leading to tubulin protofilaments polymerization. This study reported a new inhibitor‐induced‐tubulin‐morphology‐change and would provide insight into tubulin dynamic instability and also guide further study of cevipabulin.

01 Nov 2023·Bioorganic & Medicinal Chemistry

Probing a distinct druggable tubulin binding site with gatorbulins 1–7, their metabolic and physicochemical properties, and pharmacological consequences

Article

Author: Hortigüela, Rafael ; Fernando Díaz, J. ; Chen, Qi-Yin ; Cameron, Michael D. ; Luesch, Hendrik ; Fernando Díaz, J ; Seabra, Gustavo M. ; Seabra, Gustavo M ; Ratnayake, Ranjala ; Ángela Oliva, María ; Cameron, Michael D

Microtubules, consisting of α/β-tubulin heterodimers, are prime targets for anticancer drug discovery. Gatorbulin-1 (GB1, 1a) is a recently described marine natural product that targets tubulin at a new, seventh pharmacological site at the tubulin intradimer interface. Using our previously developed robust route towards GB1 (1a), we synthesized simplified, first-generation gatorbulins, GB2-7 (1b-1g) of this highly modified cyclodepsipeptide (GB1) that does not contain any proteinogenic amino acid. We systematically investigated the structure-activity relationship at the biochemical and cellular level using GB1-susceptible ovarian and cervical cancer cells. We validated that the hydroxamate moiety in the N-methyl-alanine residue is critical for activity. All other structural modifications present in GB1, including C-hydroxylation of asparagine, methylation at C-4 of proline, and sp² hybridization in dehydro-alanine, were proven to be functionally relevant. Replacement of the primary amide with a methyl ester also resulted in reduced activity, indicating the intricate scaffold optimization by the GB1-producing cyanobacterium. Inhibition of tubulin polymerization in vitro and binding affinities correlated very well, translating into differentials in cellular efficacy. We used docking and molecular dynamics to evaluate the effects of the chemical simplification at the structural level, indicating that each modification resulted in loss of target interactions, although energetically modest. Similar to cevipabulin that targets two different sites on the tubulin dimer, GB1 promotes proteasome-mediated tubulin degradation but by an unknown mechanism, presumably distinct from that of cevipabulin. Comparison with cevipabulin indicated that this compound binds to the same tubulin region as GB1 (1a), although the binding mode is distinct. Cevipabulin almost exclusively interacts with α-tubulin, including nonexchangeable GTP. In contrast, GB1 (1a) makes extensive contact and hydrogen bonds with both α- and β-chains of tubulin. GB1-7 showed excellent solubility and much higher than that of paclitaxel. Hepatic microsome stability was excellent, human cytochrome P450s were not inhibited and plasma binding was minimal with high free fractions. Passive permeability was predicted to be high based on PAMPA. Parent compound GB1 (1a) was further evaluated using a cellular model with MDCK cells stably transduced with the human efflux transporter MDR1/P-gp, showing similar permeability with and against transporter gradient, indicating that GB1 (1a) is a poor P-gp substrate.

15 Feb 2023·British Journal of Surgery

A randomized clinical trial of isolated ambulatory phlebectomy versus saphenous thermal ablation with concomitant phlebectomy (SAPTAP Trial)

Article

Author: Nijsten, Tamar E C ; Bos van den, R R ; Hamann, S A S ; Scheerders, E R Y ; van der Velden, Simone K ; Roos De, K P ; Goossens, Lucas M A ; Mik de, L ; Maeseneer de, M G R ; van den Bos, Renate R ; Hamann, Sterre A S ; Malskat, Wendy S J ; Scheerders, Eveline R Y ; de Maeseneer, Marianne G R ; Koppen, S ; Velden van der, S K ; de Mik, Linda ; Malskat, W S J ; Shadid, N H ; Wolff, O ; Gaastra, M T W

AbstractBackgroundCurrent treatment of patients with saphenous trunk and tributary incompetence consists of truncal ablation with concomitant, delayed or no treatment of the tributary. However, reflux of the saphenous trunk may be reversible after treatment of the incompetent tributary. The aim of this study was to determine whether single ambulatory phlebectomy with or without delayed endovenous truncal ablation (SAP) is non-inferior to thermal endovenous ablation with concomitant phlebectomy (TAP), and whether SAP is a cost-effective alternative to TAP.MethodsA multicentre, non-inferiority RCT was conducted in patients with an incompetent great saphenous vein or anterior accessory saphenous vein with one or more incompetent tributaries. Participants were randomized to receive SAP or TAP. After 9 months, additional truncal treatment was considered for SAP patients with remaining symptoms. The primary outcome was VEnous INsufficiency Epidemiological and Economic Study Quality of Life/Symptoms (VEINES-QOL/Sym score) after 12 months. Secondary outcomes were, among others, cost-effectiveness, perceived improvement of symptoms, and anatomical success.ResultsSome 464 patients received the allocated treatment (SAP 227, TAP 237). VEINES-QOL scores were 52.7 (95 per cent c.i. 51.9 to 53.9) for SAP and 53.8 (53.3 to 55.1) for TAP; VEINES-Sym scores were 53.5 (52.6 to 54.4) and 54.2 (54.0 to 55.6) respectively. Fifty-eight patients (25.6 per cent) in the SAP group received additional truncal ablation. Treatment with SAP was less costly than treatment with TAP.ConclusionOne year after treatment, participants who underwent SAP had non-inferior health-related quality of life compared with those who had TAP. Treatment with SAP was a cost-effective alternative to TAP at 12 months.Registration numberNTR 4821 (www.trialregister.nl).

100 Deals associated with Cevipabulin fumarate

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	US	Wyeth AB	01 May 2005

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