Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Fairweather, Alisa E.R.; Goetz, Daniel B.; Schroeder, Chloe M.; Bhuiyan, Nazmul H.; Varney, Michelle L.; Wiemer, David F.; Holstein, Sarah A.

doi:10.1016/j.bmc.2021.116307

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…As an alternative strategy by which to target protein homeostasis in MM, we have focused on the development of geranylgeranyl diphosphate synthase (GGDPS) inhibitors (GGSIs) [ 12 – 21 ]. In the isoprenoid biosynthetic pathway (IBP), GGDPS catalyzes the synthesis of the isoprenoid donor (GGPP) which in turn is covalently linked to the target Rab proteins by the enzyme geranylgeranyl transferase (GGTase) II.…”

Section: Introductionmentioning

confidence: 99%

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

et al. 2022

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Background Multiple myeloma (MM) remains an incurable malignancy, despite the advent of therapies such as proteosome inhibitors (PIs) that disrupt protein homeostasis and induce ER stress. We have pursued inhibition of geranylgeranyl diphosphate synthase (GGDPS) as a novel mechanism by which to target protein homeostasis in MM cells. GGDPS inhibitors (GGSI) disrupt Rab geranylgeranylation, which in turn results in perturbation of Rab-mediated protein trafficking, leading to accumulation of intracellular monoclonal protein, induction of ER stress and apoptosis. Our lead GGSI, RAM2061, has demonstrated favorable pharmacokinetic properties and in vivo efficacy. Here we sought to evaluate if combination therapy with GGSI and PI would result in enhanced disruption of the unfolded protein response (UPR) and increase anti-MM efficacy. Methods MTT assays were conducted to evaluate the cytotoxic effects of combining RAM2061 with bortezomib in human MM cells. The effects of RAM2061 and/or PI (bortezomib or carfilzomib) on markers of UPR and apoptosis were evaluated by a combination of immunoblot (ATF4, IRE1, p-eIF2a, cleaved caspases and PARP), RT-PCR (ATF4, ATF6, CHOP, PERK, IRE1) and flow cytometry (Annexin-V). Induction of immunogenic cell death (ICD) was assessed by immunoblot (HMGB1 release) and flow cytometry (calreticulin translocation). Cell assays were performed using both concurrent and sequential incubation with PIs. To evaluate the in vivo activity of GGSI/PI, a flank xenograft using MM.1S cells was performed. Results Isobologram analysis of cytotoxicity data revealed that sequential treatment of bortezomib with RAM2061 has a synergistic effect in MM cells, while concurrent treatment was primarily additive or mildly antagonistic. The effect of PIs on augmenting RAM2061-induced upregulation of UPR and apoptotic markers was dependent on timing of the PI exposure. Combination treatment with RAM2061 and bortezomib enhanced activation of ICD pathway markers. Lastly, combination treatment slowed MM tumor growth and lengthened survival in a MM xenograft model without evidence of off-target toxicity. Conclusion We demonstrate that GGSI/PI treatment can potentiate activation of the UPR and apoptotic pathway, as well as induce upregulation of markers associated with the ICD pathway. Collectively, these findings lay the groundwork for future clinical studies evaluating combination GGSI and PI therapy in patients with MM.

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Section: Introductionmentioning

confidence: 99%

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

et al. 2022

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“… 179 Extensive structure‐function analysis of a series of triazole bisphosphonates revealed the importance of alkyl chain length and olefin stereochemistry in determining inhibitor potency, and later studies showed the impact of different substituents at the α‐position. 179 , 180 , 181 , 182 , 183 , 184 …”

Section: Ggdps Inhibitorsmentioning

confidence: 99%

“…Later advancements led to the development of isoprenoid bisphosphonates containing a triazole linker group 179 . Extensive structure‐function analysis of a series of triazole bisphosphonates revealed the importance of alkyl chain length and olefin stereochemistry in determining inhibitor potency, and later studies showed the impact of different substituents at the α‐position 179–184 …”

Section: Ggdps Inhibitorsmentioning

confidence: 99%

“…179 Extensive structure-function analysis of a series of triazole bisphosphonates revealed the importance of alkyl chain length and olefin stereochemistry in determining inhibitor potency, and later studies showed the impact of different substituents at the α-position. [179][180][181][182][183][184] Other bisphosphonate-based GGSIs include thienopyrimidine bisphosphonate-based (Th-BP) compounds. The extension of the thienopyrimidine moiety was shown to increase potency due to its extension into the IPP binding site.…”

Section: Ggdps Inhibitorsmentioning

confidence: 99%

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Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

Muehlebach

Holstein

2023

Clinical & Translational Med

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Geranylgeranyl diphosphate synthase (GGDPS), an enzyme in the isoprenoid biosynthesis pathway, is responsible for the production of geranylgeranyl pyrophosphate (GGPP). GGPP serves as a substrate for the post‐translational modification (geranylgeranylation) of proteins, including those belonging to the Ras superfamily of small GTPases. These proteins play key roles in signalling pathways, cytoskeletal regulation and intracellular transport, and in the absence of the prenylation modification, cannot properly localise and function. Aberrant expression of GGDPS has been implicated in various human pathologies, including liver disease, type 2 diabetes, pulmonary disease and malignancy. Thus, this enzyme is of particular interest from a therapeutic perspective. Here, we review the physiological function of GGDPS as well as its role in pathophysiological processes. We discuss the current GGDPS inhibitors under development and the therapeutic implications of targeting this enzyme.

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“…Several generations of bisphosphonates have been developed over the years, from the first generation which did not include nitrogen atoms, such as etidronic acid ( 3 ) and clodronic acid ( 4 ), to the second and third generations of bisphosphonates, such as bisphosphonates 5 – 9 which contain nitrogen, and are more commonly referred to as N‐BPs as shown in Figure 2 (Barbosa et al, 2021). Recent developments have led to farnesyl diphosphate and geranylgeranyl diphosphate synthase inhibitors such as those shown in Figure 3 as potential new bone resorption, anti‐infective and anti‐cancer drugs (Fairweather et al, 2021; Haney et al, 2017; Matthiesen et al, 2018; Sanders et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Novel bisphosphonates via castor oil

Fayer,

Rosen,

Cermak

et al. 2023

J Americ Oil Chem Soc

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Hydroxy fatty acids (HFAs) have long been a staple component of feedstock oils with uses ranging from motor oils to food to pharmaceuticals. Castor oil, which contains the HFA ricinoleic acid as its principal component, is the most widely used source of HFA in the world. In addition, bisphosphonates are a functional moiety that has been shown to display a variety of industrial applications, ranging from use in water softeners to osteoporosis drugs, primarily due to their affinity for the calcium ion. We have long been interested in the modification of ricinoleic acid from castor oil to phosphorus derivatives, including α‐hydroxy phosphonates and phosphonic acids, and have now accomplished the synthesis of a family of ricinoleic‐derived bisphosphonates: one that retains the cis alkene found in ricinoleic acid and one where the alkene has undergone hydrogenation. These compounds have been produced in high yields and high purity and the synthesis of these compounds is reported.

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Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Cited by 7 publications

References 43 publications

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

Novel bisphosphonates via castor oil

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