한빛사논문
- 조회922
Minhyuk Park a, Donghyo Kim a, Inhae Kim b, Sin-Hyeog Im a,b, Sanguk Kim a,*
aDepartment of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea
bImmunoBiome Inc., Pohang, South Korea
*Corresponding author : Sanguk Kim
Abstract
Background: Poor translation between in vitro and clinical studies due to the cells/humans discrepancy in drug target perturbation effects leads to safety failures in clinical trials, thus increasing drug development costs and reducing patients' life quality. Therefore, developing a predictive model for drug approval considering the cells/humans discrepancy is needed to reduce drug attrition rates in clinical trials.
Methods: Our machine learning framework predicts drug approval in clinical trials based on the cells/humans discrepancy in drug target perturbation effects. To evaluate the discrepancy to predict drug approval (1404 approved and 1070 unapproved drugs), we analysed CRISPR-Cas9 knockout and loss-of-function mutation rate-based gene perturbation effects on cells and humans, respectively. To validate the risk of drug targets with the cells/humans discrepancy, we examined the targets of failed and withdrawn drugs due to safety problems.
Findings: Drug approvals in clinical trials were correlated with the cells/humans discrepancy in gene perturbation effects. Genes tolerant to perturbation effects on cells but intolerant to those on humans were associated with failed drug targets. Furthermore, genes with the cells/humans discrepancy were related to drugs withdrawn due to severe side effects. Motivated by previous studies assessing drug safety through chemical properties, we improved drug approval prediction by integrating chemical information with the cells/humans discrepancy.
Interpretation: The cells/humans discrepancy in gene perturbation effects facilitates drug approval prediction and explains drug safety failures in clinical trials.
논문정보
- Research article
- 2023년 07월 (BRIC 등록일 2023-07-17)
- 국내 연구진
- 생명과학 > 구조생물 및 생물물리학
댓글 작성 로그인
팝업 닫기관련 링크
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
