Preclinical pharmacokinetics, CYP phenotyping, and tissue distribution study of novel anti-breast cancer candidate S-011-1559

Abstract

1. S-011-1559 is a tyrosine-derived novel benzoxazine CDRI molecule targeted to the oestrogen-related receptor (ER-α/β) modulator in breast cancer. To explore the pharmacokinetics of S-011-1559, a selective and sensitive bioanalytical method using LC-MS/MS was established and validated in different biological matrices of female rats.

2. Blood-to-plasma ratio and plasma protein binding (PPB) of S-011-1559 were found to be <1 and >97% in both rats and humans, respectively. The human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) binding was found in the range of > 68 to 45% and >14% respectively. Half-life and intrinsic clearance by microsomal stability study were found to be 28.83 min and 0.05 mL/min/mg in rats, 78.35 min and 0.036 mL/min/mg in humans, respectively. The IC₅₀ value of S-011-1559 against CYP isoforms was revealed to moderately inhibit CYP2D6 by a reversible non-competitive mechanism.

3. Tissue distribution of S-011-1559 on single intravenous injection at 2 mg/kg was found in the order of C lungs > C mammary gland > C spleen > C heart > C kidney > C liver > C brain.

4. The data from the present study provides crucial information about S-011-1559 for further development as a novel potential drug candidate in modulating ER-α/β receptors of lung and breast neoplasia.

Keywords:

• S-011-1559
• triple-negative breast cancer
• HSA drug binding
• CYP phenotyping
• pharmacokinetics
• tissue distribution

Acknowledgments

The authors thank the CSIR-CDRI Director, for providing facilities and infrastructure for the study. The author SKV is also thankful to the Council of Scientific and Industrial Research (CSIR) for providing fellowship and grateful to JNU, New Delhi for academic support. AB, SA, SNS, and ACB are thankful to ICMR for providing the fellowship. UGC is being acknowledged by MK for providing funds. AM and ADC are thankful to DST-INSPIRE for supporting with necessary funds. CSIR-CDRI communication number for this manuscript is 94/2022/RSB.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the CSIR (Fund Number: 19/06/2016(i)EU-V), Indian Council of Medical Research (ICMR), Govt. of India (Fund Number: 3/1/3(2)/OPH/2020-NCD-II), Department of Science and Technology, India (Fund Number: DST/INSPIRE Fellowship/2019/IF190774).