Sensitive liquid chromatography/tandem mass spectrometry method for the determination of two novel highly lipophilic anticancer drug candidates in rat plasma and tissues

Q4 · MEDICINE

Article

Author: Chen, Yanhua ; Hooshfar, Shirin ; Gera, Lajos ; Linzey, Michael R. ; Mamouni, Kenza ; Li, Xin ; Bartlett, Michael G. ; Wu, Daqing ; Olorunyolemi, Oluwasegun ; Yang, Yang

AbstractA simple and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC‐ESI‐MS/MS) method was developed and validated for determination of two highly lipophilic anticancer drug candidates, LG1980 and GH501, in rat plasma and tissues (liver, kidney and femur bones). LG1980 and GH501 were extracted from rat plasma and tissue homogenates using liquid–liquid extraction. The method provided a linear range of 1.0–200.0 ng/mL for GH501 in plasma and LG1980 in plasma and liver. For both analytes in other tissue homogenates the linear range was 2.0–400.0 ng/mL. The method was validated with precision within 15% relative standard deviation, accuracy within 15% relative error and a consistent recovery. This method has been successfully applied in two preclinical studies for LG1980 and GH501 to determine their concentrations in rat plasma, liver, kidney and bone over 24 h after intravenous injection of compounds.

British Journal of Cancer

Novel Skp1 inhibitor has potent preclinical efficacy against castration-resistant prostate cancer

Article

Author: Xie, Zhong-Ru ; Chen, Yanhua ; Cook, Nicholas ; Zhao, Rui ; Danaher, Alira ; Nelson, Peter S ; Zhu, Jedidiah ; Kucuk, Omer ; Bai, Lijuan ; Zhou, Jia ; Bao, Qichao ; Liu, Degang ; Mamouni, Kenza ; Wu, Daqing ; Bowen, Nathan J ; Coleman, Ilsa M ; Wu, Yifei ; Sautto, Giuseppe A ; Osunkoya, Adeboye O ; Li, Dehong ; Li, Xin ; Grayson, Skylar ; Gera, Lajos

BACKGROUNDMetastatic, castration-resistant prostate cancer (mCRPC) directly contributes to the mortality and morbidity of prostate cancer. It is imperative to identify new molecular targets and discover effective therapeutic agents against lethal mCRPC.METHODSThe anticancer activities and mechanism of action of the small-molecule lead compound were investigated in preclinical models of human prostate cancer. Immunohistochemistry was employed to determine the expression of S-phase kinase-associated protein 1 (Skp1) in human prostate tissues.RESULTSGH501 demonstrates nanomolar potency in the NCI-60 human cancer cell panel and multiple mCRPC cell lines with diverse genetic backgrounds, including those resistant to androgen deprivation therapy drugs. Mechanistically, GH501 may bind Skp1 and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2) within the Skp1-Cullin1-F-box protein ubiquitin ligase complexes (SCF), thereby affecting multiple oncogenic signals implicated in mCRPC progression, including p21, p27, β-catenin, cyclin D1, enhancer of zeste homolog 2 (EZH2), c-Myc, and survivin. GH501 exhibits excellent in vitro and in vivo safety pharmacology, and GH501 monotherapy effectively inhibits the in vivo growth of cell- and patient-derived xenografts in intraosseous and subcutaneous models. Skp1 expression is significantly increased in human prostate cancer specimens.CONCLUSIONThese results indicate that interrupting Skp1-Skp2 interaction is an effective approach to target mCRPC and warrant further preclinical development of GH501 as a promising therapeutic candidate.

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Indication	Highest Phase	Country/Location	Organization	Date
Castration-Resistant Prostatic Cancer	Preclinical	United States	Sartorius Corp.	04 Apr 2023
Castration-Resistant Prostatic Cancer	Preclinical	United States	Clark Atlanta University	04 Apr 2023
Metastatic Prostate Carcinoma	Discovery	United States	MetCure Therapeutics LLC	-

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