Related Experiment Video
Updated: Apr 20, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Development and validation of method for TH588 and TH287, potent MTH1 inhibitors and new anti-cancer agents, for
Aljona Saleh1, Camilla Gökturk2, Ulrika Warpman-Berglund2
1Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
Abstract:
MTH1 is a protein that is required for cancer cell survival and is overexpressed in cancer cells. TH588 and TH287 are two new compounds that inhibit the MTH1 protein. The inhibitors were tested in pharmacokinetic studies on mice. A bioanalytical method was developed and validated for determination in mice plasma. The method was based on protein precipitation followed by LC-MS/MS analysis. The separation was performed on an Ascentis Express RP-Amide C18 column. The mass spectrometer was operated in positive electrospray ionization mode and the analytes were determined with multiple reaction monitoring (MRM). Abundant monoisotopic fragments were used for quantification. Two additional fragments were used for conformational analysis. The recovery of the compounds in plasma varied between 61 and 91% and the matrix effects were low and ranged between -3% and +2%. The method showed to be selective, linear, accurate and precise, and applicable for preclinical pharmacokinetic studies of TH588 and TH287 in mouse plasma. Half-life (T1/2) was ≤3.5h and maximum concentration (Cmax) ranged between 0.82 and 338μM for the different administration routes and compounds.
Insights
New compounds TH588 and TH287 inhibit MTH1, a protein crucial for cancer cell survival. A validated bioanalytical method enables preclinical pharmacokinetic studies of these MTH1 inhibitors in mice plasma.
Area of Science:
- Biochemistry
- Pharmacology
- Analytical Chemistry
Background:
- Mutant-like 1 (MTH1) protein is essential for cancer cell survival.
- MTH1 is overexpressed in various cancer types.
- TH588 and TH287 are novel MTH1 protein inhibitors.
Purpose of the Study:
- To develop and validate a bioanalytical method for quantifying TH588 and TH287 in mouse plasma.
- To assess the pharmacokinetic profiles of TH588 and TH287 in preclinical mouse models.
Main Methods:
- Protein precipitation followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
- Analysis using an Ascentis Express RP-Amide C18 column and positive electrospray ionization.
- Quantification via multiple reaction monitoring (MRM) using abundant monoisotopic fragments.
Main Results:
- The validated method demonstrated high selectivity, linearity, accuracy, and precision.
- Low matrix effects (-3% to +2%) and good recovery (61% to 91%) were observed.
- Pharmacokinetic parameters showed half-life (T1/2) ≤3.5h and maximum concentration (Cmax) ranging from 0.82 to 338μM.
Conclusions:
- The developed LC-MS/MS method is suitable for preclinical pharmacokinetic studies of TH588 and TH287.
- These MTH1 inhibitors exhibit promising pharmacokinetic properties in mice.
- Further investigation into TH588 and TH287 for cancer therapy is warranted.
More Related Videos
11:02Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
08:53In Vivo Immunofluorescence Localization for Assessment of Therapeutic and Diagnostic Antibody Biodistribution in Cancer Research
Published on: September 16, 2019
