Delving into the Latest Updates on Karonudib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

MTH1

Mechanism

MTH1 antagonists(nudix hydrolase 1 antagonists)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Acute Myeloid LeukemiaSolid tumor

Inactive Indication-

Originator Organization-

Active Organization-

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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The primary objective of this study is to determine safety and tolerability of Karonudib for the treatment of hematological malignancies.
Secondary objectives are to determine a recommended RP2D and schedule for further development of Karonudib, to determine the pharmacokinetics of Karonudib, to look for evidence of treatment efficacy. Overall survival will also be recorded.

Start Date03 Dec 2019

Sponsor / Collaborator-

NCT03036228 / RecruitingPhase 1IIT

MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class

Primary Objective
• To determine the safety and tolerability of Karonudib (TH1579) in escalating doses for the treatment of patients with advanced solid malignant tumours.
Secondary Objective
To define DLT and MTD.
To determine a recommended phase 2 dose (RP2D) and schedule.
To determine the pharmacokinetics of Karonudib.
To determine preliminary signs of clinical efficacy of Karonudib.
To determine overall survival.

Start Date14 Jan 2017

Sponsor / Collaborator-

100 Clinical Results associated with Karonudib

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100 Translational Medicine associated with Karonudib

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100 Patents (Medical) associated with Karonudib

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18

Literatures (Medical) associated with Karonudib

12 Oct 2023·Cancers

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma.

Article

Author: Vaitsi, Photene C ; Kosti, Chrysavgi N ; Psarra, Katherina ; Pappas, Apostolos G ; Kalomenidis, Ioannis T ; Magkouta, Sophia F ; Iliopoulou, Marianthi P

BACKGROUNDMTH1 protects tumor cells and their supporting endothelium from lethal DNA damage triggered by oxidative stress in the tumor microenvironment, thus promoting tumor growth. The impact of MTH1 on the tumor-related immune compartment remains unknown. We hypothesized that MTH1 regulates immune fitness and therefore enhances the activity of currently used immunotherapeutic regimens.METHODSOur hypotheses were validated in two syngeneic murine mesothelioma models using the clinically relevant MTH1 inhibitor, karonudib. We also examined the effect of combined MTH1 and PD-L1 blockade in mesothelioma progression, focusing on the main immune players.RESULTSKaronudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy.CONCLUSIONSCombined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma.

01 Jan 2023·Targeting the DNA Damage Response for Cancer Therapy

Mitotic MTH1 Inhibitors in Treatment of Cancer

Article

Author: Helleday, Thomas

The DNA damage response (DDR) protein MTH1 is sanitising the oxidized dNTP pool and preventing incorporation of oxidative damage into DNA and has an emerging role in mitosis. It is a stress-induced protein and often found to be overexpressed in cancer. Mitotic MTH1 inhibitors arrest cells in mitosis and result in incorporation of oxidative damage into DNA and selective killing of cancer cells. Here, I discuss the leading mitotic MTH1 inhibitor TH1579 (OXC-101, karonudib), now being evaluated in clinical trials, and describe its dual effect on mitosis and incorporation of oxidative DNA damage in cancer cells. I describe why MTH1 inhibitors that solely inhibits the enzyme activity fail to kill cancer cells and discuss if MTH1 is a valid target for cancer treatment. I discuss emerging roles of MTH1 in regulating tubulin polymerisation and mitosis and the necessity of developing the basic science insights along with translational efforts. I also give a perspective on how edgetic perturbation is making target validation difficult in the DDR field.

04 May 2022·Molecular Cancer Therapeutics

Inhibition of Oxidized Nucleotide Sanitation By TH1579 and Conventional Chemotherapy Cooperatively Enhance Oxidative DNA Damage and Survival in AML

Article

Author: Vittori, Camilla ; Estruch, Montserrat ; Warpman Berglund, Ulrika ; Sanjiv, Kumar ; Helleday, Thomas ; Centio, Anders ; Engelhard, Sophia ; Theilgaard-Mönch, Kim ; Reckzeh, Kristian

AbstractCurrently, the majority of patients with acute myeloid leukemia (AML) still die of their disease due to primary resistance or relapse toward conventional reactive oxygen species (ROS)- and DNA damage–inducing chemotherapy regimens. Herein, we explored the therapeutic potential to enhance chemotherapy response in AML, by targeting the ROS scavenger enzyme MutT homolog 1 (MTH1, NUDT1), which protects cellular integrity through prevention of fatal chemotherapy-induced oxidative DNA damage. We demonstrate that MTH1 is a potential druggable target expressed by the majority of patients with AML and the inv(16)/KITD816Y AML mouse model mimicking the genetics of patients with AML exhibiting poor response to standard chemotherapy (i.e., anthracycline & cytarabine). Strikingly, combinatorial treatment of inv(16)/KITD816Y AML cells with the MTH1 inhibitor TH1579 and ROS- and DNA damage-inducing standard chemotherapy induced growth arrest and incorporated oxidized nucleotides into DNA leading to significantly increased DNA damage. Consistently, TH1579 and chemotherapy synergistically inhibited growth of clonogenic inv(16)/KITD816Y AML cells without substantially inhibiting normal clonogenic bone marrow cells. In addition, combinatorial treatment of inv(16)/KITD816Y AML mice with TH1579 and chemotherapy significantly reduced AML burden and prolonged survival compared with untreated or single treated mice. In conclusion, our study provides a rationale for future clinical studies combining standard AML chemotherapy with TH1579 to boost standard chemotherapy response in patients with AML. Moreover, other cancer entities treated with ROS- and DNA damage–inducing chemo- or radiotherapies might benefit therapeutically from complementary treatment with TH1579.

100 Deals associated with Karonudib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 1	-	-	23 Mar 2022
Solid tumor	Phase 1	-	-	23 Mar 2022

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03036228 (AACR2023) Manual	Phase 1	Advanced Malignant Solid Neoplasm First line	-	OXC-101	(uadarqnksc) = kltskrfxly ffdjnqecmd (gkeiomheul ) View more	Positive	14 Apr 2023