Clinical development of IDH1 inhibitors for cancer therapy

Zarei, Mahsa; Hue, Jonathan J.; Hajihassani, Omid; Graor, Hallie J.; Katayama, Erryk S.; Loftus, Alexander W.; Bajor, David L.; Rothermel, Luke D.; Vaziri‐Gohar, Ali; Winter, Jordan M.

doi:10.1016/j.ctrv.2021.102334

Cited by 26 publications

(15 citation statements)

References 86 publications

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“…Ivosidenib was selected for downstream experiments since this drug performed well compared with other tested compounds (Fig. 4a ), is well tolerated in patients and is already FDA approved for medically refractory IDH1-mutant acute myeloid leukemia and IDH1-mutant cholangiocarcinoma 49 – 51 . The drug was also highly potent in a cell-free wtIDH1 activity assay when Mg 2+ concentrations were reduced to 0.1 mM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors

et al. 2022

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Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

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Section: Resultsmentioning

confidence: 99%

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors

et al. 2022

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“…5% for stability studies. No-carrier-added fluorine-18 was produced by Curium Pharma via the [ 18 O(p, n) 18 F] nuclear reaction by irradiation of a 2.8 mL > 97%-enriched [ 18 O]H 2 O target (Bruce Technology) on a PETtrace cyclotron (16 MeV proton beam, GE healthcare). The radio TLC strips (Macherey-Nagel, Precoated TLC sheets ALUGRAM ® Xtra SIL G/UV 254 ) were developed with EtOAc/cyclohexane (80/20, v/v) and measured on a miniGITA Dual radio-TLC instrument (Elysia-Raytest).…”

Section: Radiolabelling With Iodine-125mentioning

confidence: 99%

“…The aqueous solution of [ 18 F]F − in [ 18 O]H 2 O was passed through an anion exchange resin (Sep-Pak ® Light Accell Plus QMA carbonate cartridge) preconditioned with 10 mL of ethanol, 10 mL of an aqueous solution of lithium trifluoromethanesulfonate (90 mg/mL), and 10 mL of deionised water. Then, a solution of potassium carbonate (50 µg) and lithium trifluoromethanesulfonate (10 mg) in water (550 µL) was passed through the cartridge to elute the radioactivity to the reactor before addition of anhydrous ACN (1 mL).…”

Section: Radiolabelling With Fluorine-18mentioning

confidence: 99%

“…Recently, ivosidenib also received FDA approval for locally advanced or metastatic cholangiocarcinoma with mIDH1 mutations [17]. Further mIDH inhibitors, such as AG-881 (vorasidenib, Servier/Agios Pharm., Cambridge, MA, USA), IDH305 (Novartis, Basel, Switzerland), and olutasidenib (FT-2102, Forma Therapeutics, Watertown, MA, USA), are currently under investigation in several clinical trials [5,18,19]. In parallel to the clinical validation of new targeted therapies, drug approval agencies, such as the FDA, highlight the importance of developing companion diagnostics that can influence the treatment direction.…”

Section: Introductionmentioning

confidence: 99%

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Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

et al. 2022

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Isocitrate dehydrogenases (IDHs) are metabolic enzymes commonly mutated in human cancers (glioma, acute myeloid leukaemia, chondrosarcoma, and intrahepatic cholangiocarcinoma). These mutated variants of IDH (mIDH) acquire a neomorphic activity, namely, conversion of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate involved in tumourigenesis. Thus, mIDHs have emerged as highly promising therapeutic targets, and several mIDH specific inhibitors have been developed. However, the evaluation of mIDH status, currently performed by biopsy, is essential for patient stratification and thus treatment and follow-up. We report herein the development of new radioiodinated and radiofluorinated analogues of olutasidenib (FT-2102) as tools for noninvasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging of mIDH1 up- and dysregulation in tumours. Nonradiolabelled derivatives 2 and 3 halogenated at position 6 of the quinolinone scaffold were synthesised and tested in vitro for their inhibitory potencies and selectivities in comparison with the lead compound FT-2102. Using a common organotin precursor, (S)-[125I]2 and (S)-[18F]3 were efficiently synthesised by radio-iododemetallation and copper-mediated radiofluorination, respectively. Both radiotracers were stable at room temperature in saline or DPBS solution and at 37 °C in mouse serum, allowing future planning of their in vitro and in vivo evaluations in glioma and chondrosarcoma models.

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“…Our recent studies in pancreatic cancer identified for the first time that small molecules developed as selective mutant-IDH1 inhibitors (25)(26)(27)(28), actually inhibit wtIDH1 with a high degree of potency under conditions present in the tumor microenvironment (24). Specifically, reduced magnesium levels in tumors allow mutant-IDH1 inhibitors to bind to the wtIDH1 allosteric site with greater affinity (29).…”

Section: Introductionmentioning

confidence: 99%

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma

Zarei

Hajihassani

Hue

et al. 2022

Preprint

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Malignant melanoma is one of the most common types of cancer in the United States. Despite recent and well-described progress in melanoma treatment, advanced disease still carries a poor prognosis for many patients and chemotherapy has been appropriately abandoned as a front-line option. Wild-type isocitrate dehydrogenase 1 (wtIDH1) has recently been implicated as a metabolic dependency in cancer. The enzyme is protective to cancer cells under metabolic stress, including oxidative damage by conventional chemotherapy and nutrient limitation characteristic of the tumor microenvironment. Specifically, the cytosolic enzyme generates NADPH to maintain redox homeostasis. IDH1 also supports mitochondrial function through anaplerosis of its reaction product, α-ketoglutarate. We show that melanoma patients express higher levels of the wtIDH1 enzyme compared to normal skin tissue, and elevated wtIDH1 expression portends poor patient survival. Knockdown of IDH1 by RNA interference inhibited cell proliferation and migration under low nutrient levels. Suppression of IDH1 expression in melanoma also decreased NADPH and glutathione levels, resulting in increased reactive oxygen species. An FDA-approved inhibitor of mutant IDH1, ivosidenib (AG-120), exhibited potent anti-wtIDH1 properties under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura. Similarly, findings were replicated in murine models of melanoma. Further, wtIDH1 inhibition was synergistic to conventional anti-melanoma chemotherapy in pre-clinical models. This work points to a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma.

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Clinical development of IDH1 inhibitors for cancer therapy

Cited by 26 publications

References 86 publications

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors

Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma

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