Early-stage drug discovery is often hindered by two major challenges. The first is identifying initial hits against difficult-to-drug targets. The second is advancing HTS-derived hits into high-quality lead candidates. Many hits fail due to off-target activity, poor ADME-Tox profiles, limited SAR opportunities, or insufficient tractability for medicinal chemistry optimization. These limitations can slow project progression and reduce the likelihood of discovering differentiated candidates, highlighting the growing interest in innovative approaches to improve both hit identification and hit expansion.

Translational risk remains a major challenge in obesity and kidney disease drug development, often leading to uncertainty in preclinical decision-making. In obesity, the success of GLP-1 therapies has set a new benchmark, driving the development of both novel mechanisms beyond GLP-1 and combination strategies to address its limitations, including nausea, muscle loss, and weight regain. However, conventional preclinical evaluation based on body weight alone often fails to distinguish true pharmacological efficacy from adverse effect–driven outcomes.