Highlighting the mechanistic role of Olutasidenib (FT-2102) in the selective inhibition of mutated isocitrate dehydrogenase 1 (mIDH1) in cancer therapy

Salifu, Elliasu Y.; Agoni, Clement

doi:10.1016/j.imu.2021.100829

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…The introduction of a fluorine atom in place of chlorine also resulted in good retention of inhibitory potency (22.7 ± 5.2 nM) despite an approximate fourfold decrease when compared with iodinated compound (S)-2. As the 6-chloro substituent of the quinolinone ring of FT-2102 is positioned in a hydrophobic pocket [24,26], the better inhibitory potency of (S)-2 compared with (S)-3 could be explained by the ability of iodine, due to its lower electronegativity, to form stronger hydrophobic interactions with the With replacement of chlorine with iodine, compound (S)-2 maintained similar potency for all tested IDHs as that of the lead compound FT-2102 (5.23 ± 0.75 nM vs. 4.88 ± 1.63 nM, respectively, on IDH1 R132H and 160 ± 24 nM vs. 178 ± 70 nM, respectively, on IDH1 R132C). The introduction of a fluorine atom in place of chlorine also resulted in good retention of inhibitory potency (22.7 ± 5.2 nM) despite an approximate fourfold decrease when compared with iodinated compound (S)-2.…”

Section: Biological Evaluationmentioning

confidence: 99%

“…The introduction of a fluorine atom in place of chlorine also resulted in good retention of inhibitory potency (22.7 ± 5.2 nM) despite an approximate fourfold decrease when compared with iodinated compound (S)-2. As the 6-chloro substituent of the quinolinone ring of FT-2102 is positioned in a hydrophobic pocket [24,26], the better inhibitory potency of (S)-2 compared with (S)-3 could be explained by the ability of iodine, due to its lower electronegativity, to form stronger hydrophobic interactions with the neighbouring nonpolar amino acids in the active site. As expected, the (R)-methyl enantiomers were substantially less potent, with at least 30-fold lower inhibition of the two mutants (IC 50 : 323 nM and 698 nM on IDH1 R132H and >10,000 nM on IDH1 R132C).…”

Section: Biological Evaluationmentioning

confidence: 99%

“…Structure-activity relationship studies have provided an extensive elucidation of the interaction mode of FT-2102 with the mIDH1 R132H enzyme [24][25][26]. Accordingly, positions 6 and 7 of the FT-2102 quinolinone core, oriented towards a hydrophobic pocket, can be modified with the lower risk of impact on the biological target affinity.…”

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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Section: Biological Evaluationmentioning

confidence: 99%

“…The introduction of a fluorine atom in place of chlorine also resulted in good retention of inhibitory potency (22.7 ± 5.2 nM) despite an approximate fourfold decrease when compared with iodinated compound (S)-2. As the 6-chloro substituent of the quinolinone ring of FT-2102 is positioned in a hydrophobic pocket [24,26], the better inhibitory potency of (S)-2 compared with (S)-3 could be explained by the ability of iodine, due to its lower electronegativity, to form stronger hydrophobic interactions with the neighbouring nonpolar amino acids in the active site. As expected, the (R)-methyl enantiomers were substantially less potent, with at least 30-fold lower inhibition of the two mutants (IC 50 : 323 nM and 698 nM on IDH1 R132H and >10,000 nM on IDH1 R132C).…”

Section: Biological Evaluationmentioning

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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“…However, as summarized in Figure 5 and described in more detail in Section 7 , most mIDH1-selective inhibitors have been shown or are thought to target a common induced-fit pocket adjacent to the substrate binding site, which may also be present in the wildtype enzyme but appears to be more accessible in mutated isoforms. While the exact residues involved ( Figure 5 A), as well as the mode of binding to this pocket (e.g., competitive or non-competitive with respect to α-KG and/or Mg 2+ ) can differ between inhibitors, they appear to invariably lock the enzyme in inactive states, as exemplified in Figure 5 B [ 63 , 64 , 65 , 66 ]. Selectivity for mutant over wildtype enzymes may at least in part arise from mutation-induced destabilization of a regulatory segment (regulatory segment 2 comprised residues 271–286), which is normally held in place by the interaction of Asp 279 with Arg 132 (i.e., the mutated residue) and restricts access to the allosteric pocket in inactive wildtype enzymes [ 66 , 67 , 68 ] ( Figure 5 B inset).…”

Section: Considerations For the Development Of Midh-selective Pet-tra...mentioning

confidence: 99%

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

2023

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Gliomas are the most common primary brain tumors in adults. A diffuse infiltrative growth pattern and high resistance to therapy make them largely incurable, but there are significant differences in the prognosis of patients with different subtypes of glioma. Mutations in isocitrate dehydrogenase (IDH) have been recognized as an important biomarker for glioma classification and a potential therapeutic target. However, current clinical methods for detecting mutated IDH (mIDH) require invasive tissue sampling and cannot be used for follow-up examinations or longitudinal studies. PET imaging could be a promising approach for non-invasive assessment of the IDH status in gliomas, owing to the availability of various mIDH-selective inhibitors as potential leads for the development of PET tracers. In the present review, we summarize the rationale for the development of mIDH-selective PET probes, describe their potential applications beyond the assessment of the IDH status and highlight potential challenges that may complicate tracer development. In addition, we compile the major chemical classes of mIDH-selective inhibitors that have been described to date and briefly consider possible strategies for radiolabeling of the most promising candidates. Where available, we also summarize previous studies with radiolabeled analogs of mIDH inhibitors and assess their suitability for PET imaging in gliomas.

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“…Prior to molecular docking, the energy grid was generated by enclosing the conserved residues of mIDH2 protein reported in the literature. For instance, the conserved residues incorporated in the grid include Val161, Trp164, Val294, Val297, Leu298, Trp306, Glu316, Ile319, Leu320 and Gly323 [40,41]. The grid coordinates (-32.31, -14.10, -27.02) encompassing these residues serve as the binding site for the library compounds during the course of molecular docking.…”

Section: Virtual Screeningmentioning

confidence: 99%

Exploration of natural product database for the identification of potent inhibitor against IDH2 mutational variants for glioma therapy

Murali

Ramanathan

2022

J Mol Model

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Mutation in Isocitrate dehydrogenase 2 (mIDH2) is an oncogenic driver prevalently reported in various cancer types including gliomas. To date, enasidenib is the only FDA-approved drug widely used as a mIDH2 (R140Q) inhibitor. However, dose-limiting toxicity and modest brain penetrating capability restrict its use as a plausible mIDH2 inhibitor. Furthermore, secondary site mutations (Q316E and I319M) were identi ed in patients with enasidenib treatments resulting in acquired therapeutic resistance. Hence, in the present investigation, we aimed to identify novel and potent drug-like compounds to overcome the existing drawbacks using an integrated insilico strategy. A sum of 1574 natural compounds from the Naturally occurring Plant-based Anti-cancerous Compound Activity Target (NPACT) database was proclaimed and subjected to screening processes such as similarity calculations and molecular docking. The binding a nities of the resultant natural compounds were rescored using MM-GBSA and RF scoring functions. The toxicity and drug likeliness of the lead compounds were investigated using ADMET properties. Eventually, the integrated in-silico approach resulted in a lead molecule namely squalene (NPACT00954) against mIDH2 protein. The screened compound was subjected to mutational analysis accomplishing second-site mutations. Interestingly, squalene exhibited appreciable binding a nity alongside good brain penetrating potential than enasidenib. Indeed, the reproducibility and signi cance of our results are examined by running 3 replica 100ns simulations per system using the random initial velocities of the atoms generated by Maxwell distribution at a given temperature. Collectively, the results from our study speculate that squalene could be persuasively translated for its use as a rational therapeutic agent against mIDH2 variants.

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Highlighting the mechanistic role of Olutasidenib (FT-2102) in the selective inhibition of mutated isocitrate dehydrogenase 1 (mIDH1) in cancer therapy

Cited by 11 publications

References 27 publications

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

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

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

Exploration of natural product database for the identification of potent inhibitor against IDH2 mutational variants for glioma therapy

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