Delving into the Latest Updates on CZ-48 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Camptothecin-20-O-Propionate Hydrate

Target

TOP1

Mechanism

TOP1 inhibitors(DNA topoisomerase I inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmLymphomaSolid tumor

Originator Organization

NMT Pharmaceuticals Pte Ltd

Active Organization-

Inactive Organization

Cao Pharmaceuticals, Inc.Startup

CARA Therapeutics, Inc.NMT Pharmaceuticals Pte Ltd

+ [1]

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC23H20N2O5

InChIKeyYCNIQYLWIPCLNY-QHCPKHFHSA-N

CAS Registry194414-69-2

This is a phase I and pharmacology study of Camptothecin-20-O-Propionate Hydrate (CZ48) in Patients with Solid Tumors or Lymphoma.
OBJECTIVES
Primary:
To describe the dose limiting toxicities and adverse event profile of Camptothecin-20-O-Propionate hydrate (CZ48) administered orally every day.
To determine Phase II recommended dose of Camptothecin-20-O-Propionate hydrate (CZ48) administered orally every day.
Secondary:
To perform a pharmacokinetic study of orally administered CZ48 in the plasma.
To assess responses by RECIST criteria.
To follow patients for survival.

Start Date01 Sep 2008

Sponsor / Collaborator

New Mexico Cancer Care Alliance

[+1]

NCT02575638 / Unknown statusPhase 1

Phase I Clinical Trial of Camptothecin-20-O-Propionate Hydrate (CZ48)

This is a single-arm, non-randomized feasibility and Phase I trial of 20(S) Camptothecin Propionate administered orally. CZ48 will be administered in successive cohorts of 1 patient per participating site until hints of toxicity (grade 2 or worse adverse events related to the drug) are observed. Then cohorts of 3+3 patients will be treated. CZ48 will be administered orally daily (1 course = 4 weeks). No pre-medications will be administered. Patients will be asked to drink up to one gallon of fluid daily if possible to flush the bladder to mitigate cystitis. Cystitis is an anticipated toxicity as CZ48 is a pro-drug of CPT (Camptothecin)

Start Date01 Jul 2008

Sponsor / Collaborator

Cao Pharmaceuticals, Inc.Startup

[+1]

100 Clinical Results associated with CZ-48

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100 Translational Medicine associated with CZ-48

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100 Patents (Medical) associated with CZ-48

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16

Literatures (Medical) associated with CZ-48

01 Dec 2021·The FEBS JournalQ3 · BIOLOGY

Acidic pH irreversibly activates the signaling enzyme SARM1

Q3 · BIOLOGY

Article

Author: Zhao, Zhi Ying ; Wang, Qian Wen ; Tan, Yongjun ; Zhang, Dapeng ; Li, Wan Hua ; He, Wei Ming ; Hou, Yun Nan ; Zhao, Yong Juan

SARM1, an executioner in axon degeneration, is an autoinhibitory NAD‐consuming enzyme, composed of multiple domains. NMN and its analogs, CZ‐48 and VMN, are the only known activators, which can release the inhibitory ARM domain from the enzymatic TIR domain. Here, we document that acid can also activate SARM1, even more efficiently than NMN, possibly via the protonation of the negative residues. Systematic mutagenesis revealed that a single mutation, E689Q in TIR, led to the constitutive activation of SARM1. It forms a salt bridge with R216 in the neighboring ARM, maintaining the autoinhibitory structure. Using this ‘acid activation’ protocol, mutation K597E was found to inhibit activation, while H685A eliminated SARM1 catalytic activity, revealing two distinct inhibitory mechanisms. The protocol has also been applied to differentiate two classes of chemical inhibitors. NAD, dHNN, disulfiram, CHAPS, and TRX‐100 mainly inhibited the activation process, while nicotinamide and Tweens mainly inhibited SARM1 catalysis. Taken together, we demonstrate a new mechanism for SARM1 activation and decipher two distinct inhibitory mechanisms of SARM1.

01 Feb 2020·Journal of Pharmaceutical and Biomedical Analysis

The development and validation of an LC-MS/MS method for the quantification of CZ112, a prodrug of 9-Nitrocamptothecin in rat plasma

Article

Author: Zheng, Jian ; Wang, Yang ; Shao, Changmin ; Cao, Zhisong ; Wang, Ziming ; Hu, Zhiwei ; Zhang, Qiang ; Wang, Zijia ; Kou, Xiaohan ; Yu, Tao

9-Nitrocamptothecin-20-O-propionate (CZ112) and 9-Nitrocamptothecin (9NC) are the bioactive derivatives of camptothecin (CPT), an alkaloid isolated from Camptotheca acuminata, and have been confirmed to possess high anti-cancer properties. In the present study, 9NC was identified as the major metabolite of CZ112 in rat plasma through HPLC/photodiode array detection (PDA) and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. A highly sensitive LC-MS/MS method was developed and validated for the simultaneous analysis of CZ112 and 9NC in rat plasma, and camptothecin-20-O-acetate (CZ44) was used as an internal standard (IS). The calibration curves were linear (r² > 0.999) over concentrations from 2.5 to 320 ng/mL for both CZ112 and 9NC. The method had an accuracy of 96.7-109.6%, and the intra- and inter-day precision (RSD%) were 10.9% or less for CZ112 and 9NC. The stability data showed no significant degradation occurred under the experimental conditions. This method was successfully applied to the pharmacokinetic study of CZ112 and its metabolite 9NC in rat plasma after intravenous and intragastric administration. The oral bioavailability of CZ112 was 6.2 ± 3.3% (n = 6).

01 Jun 2019·Colloids and Surfaces B: BiointerfacesQ2 · ENGINEERING & TECHNOLOGY

Optimal construction and pharmacokinetic study of CZ48-loaded poly (lactic acid) microbubbles for controlled drug delivery

Q2 · ENGINEERING & TECHNOLOGY

Article

Author: Li, Si-Yang ; Guo, Sheng-Lei

CZ48, a prodrug of camptothecin (CPT) with derivative resistant to lactone hydrolysis, suffers from limited application for cancer treatment due to poor water-solubility, thus causing its low bioavailability and absorption in vivo. To echo this problem, CZ48 was incorporated into poly (lactic acid) (PLA) microbubbles via a double emulsion technique (W/O/W), and the successful loading was confirmed by X-ray diffraction (XRD) patterns and confocal laser scanning microscope (CLSM). The obtained CZ48-loaded microbubbles had a diameter ranging from 0.5 to 6.7 μm, and the encapsulation efficiency and drug-loading content were as high as 85.73 ± 2.41% and 26.07 ± 0.76%, respectively. The in vitro drug release demonstrated that only about 55% of CZ48 was released for CZ48-loaded PLA microbubbles in 48 h. In contrast, over 90% of CZ48 was released for free CZ48 crystals sample in only 5 h. Besides, in vivo pharmacokinetic studies further revealed that the availability of both CZ48 and its metabolite CPT were obviously enhanced after the incorporation of CZ48 into PLA microbubbles. To be noted, the value of AUC_0-∞ of the CZ48-loaded microbubbles was about 5-fold higher than that of free CZ48 suspension, implying a much higher anticancer effect of the CZ48-loaded microbubbles. The half-life time (T_1/2) of both CZ48 and CPT of the CZ48-loaded microbubbles were also significantly longer than that of the free CZ48, indicating a delayed release time for the microbubbles. Hence, this work promotes a promising drug carrier system for the controlled release of CZ48 as well as other drugs with poor water-solubility.

100 Deals associated with CZ-48

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	US	Christus Stehlin Foundation for Cancer Research	01 Sep 2008
Solid tumor	Phase 1	US	Cao Pharmaceuticals, Inc.Startup	01 Jul 2008
Lymphoma	Phase 1	-	NMT Pharmaceuticals Pte Ltd	-
Lymphoma	Phase 1	-	CARA Therapeutics, Inc.	-