This is a Phase I multicenter, open-label, dose-escalation study of DTP348. DTP 348 is an oral dual drug with two mechanisms of action:
carbonic anhydrase IX inhibitor which acidifies the intracellular pH through the sulfamide components
radio sensitizer of hypoxic cells through its 5-nitroimidazole moiety
The study will be conducted in 2 parts. The phase I trials will be on the standard 3+3 design first as single agent then combined with radiotherapy:
A single agent dose-escalation phase in patients with solid tumours.
A dose-escalation phase in patients with HNSCC in combination with radiotherapy
The main objective is to determine the recommended phase II dose of DTP348 in combination with radiotherapy

Start Date01 Mar 2017

Sponsor / Collaborator

Stichting Maastricht Radiation Oncology MAASTRO Clinic

100 Clinical Results associated with DH-348

100 Translational Medicine associated with DH-348

100 Patents (Medical) associated with DH-348

Literatures (Medical) associated with DH-348

01 Jan 2018·Journal of Enzyme Inhibition and Medicinal ChemistryQ2 · MEDICINE

Nitroimidazole-based inhibitors DTP338 and DTP348 are safe for zebrafish embryos and efficiently inhibit the activity of human CA IX inXenopusoocytes

Q2 · MEDICINE

ArticleOA

Author: Parkkila, Seppo ; Svorjova, Aleksandra ; Dubois, Ludwig ; Parvathaneni, Nanda Kumar ; Becker, Holger M. ; Supuran, Claudiu T. ; Barker, Harlan ; Winum, Jean-Yves ; Parikka, Mataleena ; Lambin, Philippe ; Hammaren, Milka ; Aspatwar, Ashok

Carbonic anhydrase (CA) IX is a hypoxia inducible enzyme that is highly expressed in solid tumours. Therefore, it has been considered as an anticancer target using specific chemical inhibitors. The nitroimidazoles DTP338 and DTP348 have been shown to inhibit CA IX in nanomolar range in vitro and reduce extracellular acidification in hypoxia, and impair tumour growth. We screened these compounds for toxicity using zebrafish embryos and measured their in vivo effects on human CA IX in Xenopus oocytes. In the toxicity screening, the LD₅₀ for both compounds was 3.5 mM. Neither compound showed apparent toxicity below 300 µM concentration. Above this concentration, both compounds altered the movement of zebrafish larvae. The IC₅₀ was 0.14 ± 0.02 µM for DTP338 and 19.26 ± 1.97 µM for DTP348, suggesting that these compounds efficiently inhibit CA IX in vivo. Our results suggest that these compounds can be developed as drugs for cancer therapy.

22 Sep 2015·Oncotarget

Evaluation of carbonic anhydrase IX as a therapeutic target for inhibition of breast cancer invasion and metastasis using a series ofin vitrobreast cancer models

Article

Author: Philippe Lambin ; Simon P. Langdon ; Jean-Yves Winum ; Nanda-Kumar Pavathaneni ; Carol Ward ; J. Michael Dixon ; James Meehan ; Charlene Kay ; David James Harrison ; Edward J. Jarman ; Claudiu Supuran ; Peter Mullen ; Lorna Renshaw ; In Hwa Um ; Ludwig Dubois ; Jeremy S. Thomas ; Ian H. Kunkler

Triple negative, resistant or metastatic disease are major factors in breast cancer mortality, warranting novel approaches. Carbonic anhydrase IX (CAIX) is implicated in survival, migration and invasion of breast cancer cells and inhibition provides an innovative therapeutic strategy. The efficacy of 5 novel ureido-substituted sulfamate CAIX inhibitors were assessed in increasingly complex breast cancer models, including cell lines in normoxia and hypoxia, 3D spheroids and an ex-vivo explant model utilizing fresh biopsy tissue from different breast cancer subtypes. CAIX expression was evaluated in a tissue microarray (TMA) of 92 paired lymph node and primary breast cancers and 2 inhibitors were appraised in vivo using MDA-MB-231 xenografts. FC11409B, FC9398A, FC9403, FC9396A and S4 decreased cell proliferation and migration and inhibited 3D spheroid invasion. S4, FC9398A and FC9403A inhibited or prevented invasion into collagen. FC9403A significantly reversed established invasion whilst FC9398A and DTP348 reduced xenograft growth. TMA analysis showed increased CAIX expression in triple negative cancers. These data establish CAIX inhibition as a relevant therapeutic goal in breast cancer, targeting the migratory, invasive, and metastatic potential of this disease. The use of biopsy tissue suggests efficacy against breast cancer subtypes, and should provide a useful tool in drug testing against invasive cancers.

01 Sep 2013·Radiotherapy and OncologyQ2 · MEDICINE

Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: A new concept of dual targeting drugs

Q2 · MEDICINE

Article

Author: Claudiu T. Supuran ; Natasja G. Lieuwes ; Daniela Vullo ; Ruchi Saraya ; Ludwig Dubois ; Rianne Biemans ; Marc Vooijs ; Jean-Yves Winum ; Nanda Kumar Parvathaneni ; Sarah G.J.A. Peeters ; Ala Yaromina ; Philippe Lambin ; Simon J.A. van Kuijk ; Marouan Rami

BACKGROUND AND PURPOSECarbonic anhydrase IX (CAIX) plays an important role in pH regulation processes critical for tumor cell growth and metastasis. We hypothesize that a dual targeting bioreductive nitroimidazole based anti-CAIX sulfamide drug (DH348) will reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner.MATERIAL AND METHODSThe effect of the dual targeting anti-CAIX (DH348) and its single targeting control drugs on extracellular acidification and radiosensitivity was examined in HT-29 colorectal carcinoma cells. Tumor growth and time to reach 4× start volume (T4×SV) was monitored for animals receiving DH348 (10 mg/kg) combined with tumor single dose irradiation (10 Gy).RESULTSIn vitro, DH348 reduced hypoxia-induced extracellular acidosis, but did not change hypoxic radiosensitivity. In vivo, DH348 monotherapy decreased tumor growth rate and sensitized tumors to radiation (enhancement ratio 1.50) without systemic toxicity only for CAIX expressing tumors.CONCLUSIONSA newly designed nitroimidazole and sulfamide dual targeting drug reduces hypoxic extracellular acidification, slows down tumor growth at nontoxic doses and sensitizes tumors to irradiation all in a CAIX dependent manner, suggesting no "off-target" effects. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting.

100 Deals associated with DH-348

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12741

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Head and Neck Neoplasms	Phase 1	NL	Stichting Maastricht Radiation Oncology MAASTRO Clinic	01 Mar 2017

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis