Drug development advances in human genetics-based targets

Abstract

Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome-wide association studies (GWAS), whole-exome sequencing (WES), and whole-genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics-based validated beneficial loss-of-function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

Keywords: drug development; drug target; genetic variation; genome‐wide association studies; whole‐exome sequencing; whole‐genome sequencing.

FIGURE 1

Progress in drug discovery based on targets with favorable LOF variants identified by WES, WGS, and GWAS. Targets primarily include PCSK9, ANGPTL3, HSD17B13, KHK, ASGR1, GPR75, CIDEB, and INHBE. Drug types primarily include small molecules, monoclonal antibodies, RNAi, and CRISPR gene editing therapies. The timeline is determined by the status of the target's current investigational drugs.

FIGURE 2

Biological mechanism of PCSK9 and targeted inhibition strategy. (A) When PCSK9 is present, circulating PCSK9 binds to LDLR and LDL particles through its catalytic structural domains, sequestering the LDLR for degradation in the lysosome, which in turn upregulates LDL‐C levels. When PCSK9 is not present, the LDLR loops multiple times. (B) Monoclonal antibodies (e.g., alirocumab) that bind to and inhibit soluble PCSK9 in plasma, preventing PCSK9 from binding to LDLR and causing LDLR to be degraded by the lysosome. (C) RNAi reagents (e.g., inclisiran) that prevent successful translation of PCSK9 mRNA, thereby reducing the amount of mature PCSK9 bound to LDLR. (D) In vivo gene editing of PCSK9 to induce host cell DNA double‐strand breaks to reduce PCSK9 gene expression. Copyright (2023), with permission from Elsevier. PCSK9, proprotein convertase subtilisin kexin/type 9; LDLR, low‐density lipoprotein receptor; LDLR, low‐density lipoprotein receptor.

FIGURE 3

Biological mechanism of ANGPTL3, ASGR1, HSD17B13, and KHK and targeted inhibition strategy. (A) Role of ANGPTL3 in lipoprotein metabolism and strategies for its inhibition. Upon inhibition of ANGPTL3, TG‐rich lipoproteins was hydrolyzed by free lipoprotein lipase, thereby reducing TG and other cholesterol levels. Copyright (2023), with permission from Elsevier. (B) ASGR1 regulates lipid metabolism. Downregulation of ASGR1 leads to AMPK activation and mTORC1 inhibition, which results in downregulation of SREBP and upregulation of LXR and triggers a series of responses in cholesterol metabolism, ultimately leading to a reduction in circulating cholesterol levels. (C) Role of HSD17B13 in NAFLD progression. HSD17B13 can be upregulated by LXRα/SREBP‐1c, which then recruits adipose triglyceride lipase (ATGL) and comparative gene identification‐58 (CGI‐58) to induce LD aggregation and regulate the dynamics of LDs. The HSD17B13 variant loses RDH activity and has lower phospholipid levels, showing preventive effects against NAFLD. Copyright (2023), with permission from Elsevier. (D) In vivo metabolism of fructose catalyzed by KHK. Fructose is phosphorylated by KHK to F1P, which is then catabolized by ALDOB to DHAP and glyceraldehyde. Glyceraldehyde is phosphorylated to GA3P by TKFC. DHAP and GA3P enter the glycolysis/glycogen pathway at the level of trisaccharide phosphate. Created with BioRender.com. ANGPTL3, angioprotein‐like 3; CRISPR, clustered regularly interspaced short palindromic repeats; LDL, low‐density lipoprotein; HDL, high‐density lipoprotein. ASGR1, asialoglycoprotein receptor 1; AMPK, AMP‐activated protein kinase; mTORC1, target of rapamycin complex 1; SREBP, sterol regulatory element binding protein; LXR, liver X receptor; HSD17B13, 17‐β‐hydroxysteroid dehydrogenase 13; NAFLD, nonalcoholic fatty liver disease; KHK, ketohexokinase; F1P, fructose‐1‐phosphate; ALDOB, aldolase B; DHAP, dihydroxyacetone phosphate; GA3P, glyceraldehyde 3‐phosphate; TKFC, trisaccharide kinase.