Structure-Based Design and Optimization of Novel PHGDH Inhibitors for Overcoming Erlotinib-Resistant Lung Cancer

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Phosphoglycerate dehydrogenase (PHGDH) is crucial for serine biosynthesis and is overexpressed in many cancers.
• Its aberrant expression makes PHGDH a significant therapeutic target for cancer treatment.

Purpose of the Study:

• To design and synthesize novel PHGDH inhibitors using a structure-based approach.
• To evaluate the enzymatic inhibition, cellular activity, and in vivo efficacy of these compounds.

Main Methods:

• Structure-based drug design and synthesis of PHGDH inhibitors.
• Enzymatic inhibition assays (IC50 determination).
• Cell-based assays for serine biosynthesis and proliferation.
• In vivo studies using xenograft models and X-ray crystallography.

Main Results:

• Compounds 43 (GDD-260) and 47 (GDD-261) showed potent PHGDH inhibition (IC50s 0.091 μM and 0.061 μM).
• Both compounds suppressed serine biosynthesis and exhibited antitumor activity in PHGDH-overexpressing cell lines.
• Compounds 43 and 47 demonstrated antiproliferative effects in erlotinib-resistant cell lines, synergizing with erlotinib.
• Compound 47 showed enhanced efficacy in combination with erlotinib in xenograft models.

Conclusions:

• Novel PHGDH inhibitors, particularly compounds 43 and 47, have been developed.
• These inhibitors effectively target serine biosynthesis and exhibit significant antitumor activity.
• The findings support the development of PHGDH-targeted therapies for various cancers, including drug-resistant types.