Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors

Journal of Medicinal Chemistry
Cyrus M LacbayYoula S Tsantrizos

Abstract

Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo downregulation of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma.

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Citations

Apr 27, 2019·Expert Opinion on Therapeutic Patents·Sarah A Holstein
Oct 2, 2019·Cell Death & Disease·Sherry S AgabitiAndrew J Wiemer
Feb 19, 2019·Critical Reviews in Biochemistry and Molecular Biology·Daniel D WallerYoula S Tsantrizos
Jul 14, 2019·Molecular Neurobiology·Ghulam MohammadRenu A Kowluru
Dec 23, 2019·RSC Medicinal Chemistry·Pimyupa ManaswiyoungkulPatrick T Gunning
Feb 12, 2021·European Journal of Medicinal Chemistry·Thibaut LegiganMarc Lecouvey
Mar 18, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jiajia JinYong Song
Jul 24, 2021·Bioorganic & Medicinal Chemistry·Alisa E R FairweatherSarah A Holstein
Jul 9, 2021·Journal of Medicinal Chemistry·Edyta Gendaszewska-DarmachKatarzyna M Błażewska

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