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Background: Mutations in the IDH1 gene have been shown to be an important driver in the development of acute myeloid leukemia, gliomas and certain solid tumors, which is a promising target for cancer therapy. Methods: Bidirectional recurrent neural network (BRNN) and scaffold hopping methods were used to generate new compounds, which were evaluated by principal components analysis, quantitative estimate of drug-likeness, synthetic accessibility analysis and molecular docking. ADME prediction, molecular docking and molecular dynamics simulations were used to screen candidate compounds and assess their binding affinity and binding stability with mutant IDH1 (mIDH1). Results: BRNN and scaffold hopping methods generated 3890 and 3680 new compounds, respectively. The molecules generated by the BRNN performed better in terms of molecular diversity, druggability, synthetic accessibility and docking score. From the 3890 compounds generated by the BRNN model, 10 structurally diverse drug candidates with great docking score were preserved. Molecular dynamics simulations showed that the RMSD of the four systems, M1, M2, M3 and M6, remained stable, with local flexibility and compactness similar to the positive drug. The binding free energy results indicated that compound M1 exhibited the best binding properties in all energy aspects and was the best candidate molecule among the 10 compounds. Conclusion: In present study, compounds M1, M2, M3 and M6 generated by BRNN exhibited optimal binding properties. This study is the first attempt to use deep learning to design mIDH1 inhibitors, which provides theoretical guidance for the design of mIDH1 inhibitors. [ABSTRACT FROM AUTHOR]

BackgroundMutations in the IDH1 gene have been shown to be an important driver in the development of acute myeloid leukemia, gliomas and certain solid tumors, which is a promising target for cancer therapy.MethodsBidirectional recurrent neural network (BRNN) and scaffold hopping methods were used to generate new compounds, which were evaluated by principal components analysis, quantitative estimate of drug-likeness, synthetic accessibility analysis and molecular docking. ADME prediction, molecular docking and molecular dynamics simulations were used to screen candidate compounds and assess their binding affinity and binding stability with mutant IDH1 (mIDH1).ResultsBRNN and scaffold hopping methods generated 3890 and 3680 new compounds, respectively. The molecules generated by the BRNN performed better in terms of molecular diversity, druggability, synthetic accessibility and docking score. From the 3890 compounds generated by the BRNN model, 10 structurally diverse drug candidates with great docking score were preserved. Molecular dynamics simulations showed that the RMSD of the four systems, M1, M2, M3 and M6, remained stable, with local flexibility and compactness similar to the positive drug. The binding free energy results indicated that compound M1 exhibited the best binding properties in all energy aspects and was the best candidate molecule among the 10 compounds.ConclusionIn present study, compounds M1, M2, M3 and M6 generated by BRNN exhibited optimal binding properties. This study is the first attempt to use deep learning to design mIDH1 inhibitors, which provides theoretical guidance for the design of mIDH1 inhibitors.

MutT homolog1 (MTH1) is an enzyme responsible for removing oxidized nucleotides from cells. The activation of MTH1 has been reported in a number of cancer cell types and is considered to be responsible for imparting resistance towards anticancer drugs. While there are several known mechanisms for the activation of MTH1 in cancer cells, the present study aimed to evaluate the role of mutant isocitrate dehydrogenase1 (mIDH1)-mediated reactive oxygen species (ROS) production in the activation of MTH1 in glioma cells. MTH1 was found to be upregulated in both mIDH1-expressing cells and 2-hydroxyglutarate (2-HG)-treated cells. mIDH1 and its product, 2-HG, increased the levels of ROS in cultured glioblastoma cells. Furthermore, the increased expression and activity of MTH1 were observed in glioma tissues harboring mIDH1 compared to tissues with wild-type IDH1. On the whole, the findings of the present study unveil a novel mechanism of activation of MTH1 in glioma cells harboring mutant IDH1. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A series of mIDH1 inhibitors derived from 3-pyrimidine-4-oxazolidin-2-ketone derivatives were studied by QSAR model to explore the key factors that inhibit mIDH1 activity. The generated model was cross-verified and non-cross-verified by Topomer CoMFA and HQSAR methods; the independent test set was verified by PLS method; the Topomer search technology was used for virtual screening and molecular design; and the Surflex-Dock method and ADMET technology were used for molecular docking, pharmacology and toxicity prediction of the designed drug molecules. The Topomer CoMFA and HQSAR cross-validation coefficients q2 are 0.783 and 0.784, respectively, and the non-cross-validation coefficients r2 are 0.978 and 0.934, respectively. Ten new drug molecules have been designed using Topomer search technology. The results of molecular docking and ADMET show that the newly designed drug molecules are effective. The docking situation, pharmacology and toxicity prediction results are good. The model can be used to predict the bioactivity of the same type of new compounds and their derivatives. The prediction results of molecular design, molecular docking and ADMET can provide some ideas for the design and development of novel mIDH1 inhibitor anticancer drugs, and provide certain theoretical basis of the experimental verification of new compounds in the future. Newly designed molecules after docking with corresponding proteins in the PDB library, it can explore the targets of drug molecules acting with large proteins and the related force, which is very helpful for the design of new drugs and the mechanism of drug action. [ABSTRACT FROM AUTHOR]

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.

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma. [Display omitted] • Target on mutant IDH1 in a promising method for the treatment of glioma. • The reported mIDH1 inhibitors are classified according to their binding site. • The investigation of each inhibitor's pipeline can deliver new insights for the development of mIDH1 inhibitors in treating glioma. • Binding modes and structure features of mIDH1 inhibitors in clinical could guide further drug design. • Selective mechanisms against the IDHs are emphasized in this review. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is an autosomal dominant tumour predisposition syndrome caused by a germline mutation in one of the DNA mismatch repair (MMR) genes.Patients with these mutations have an increased risk of brain tumours, the vast majority of which are glioblastomas and medulloblastomas, and their occurrence has been termed Turcot Syndrome. The case presented herein of a member of a Lynch syndrome family with an MSH2 mutation expands the spectrum of brain tumours occurring in Lynch syndrome to include low grade astrocytomas, and is the first reported case of an IDH1 (R132H) mutated brain tumour occurring in a Lynch syndrome family.

Extraneural metastases from primary brain tumors are extremely rare. We present an autopsy case that displayed a very late and unique pattern of metastasis from an anaplastic oligodendroglioma. The patient was a 74-year-old woman who was disease free for 17 years after resection of the primary oligodendroglioma. She was subsequently admitted to a hospital for heart failure where her bone marrow was found to be completely infiltrated with tumor cells, eventually resulting in disseminated intravascular coagulation. The onset was like leukemia, but the 'blast-like' cells were different from leukemic cells, and the diagnosis was difficult until autopsy. After her death, a review of her past medical history and comprehensive analysis of her primary brain tumor and aspiration biopsy/autopsy bone marrow samples with glial immunohistochemical markers, fluorescence in situ hybridization examination, and immunohistochemical/sequencing analyses of mutant IDH1 revealed the accurate diagnosis. The metastatic tumor in her bone marrow was finally diagnosed as bone metastasis from the primary anaplastic oligodendroglioma. Although metastatic oligodendroglioma is very rare, it should be noted that this condition displays a propensity for bone and bone marrow and can present with features similar to those of leukemia after a long latency period. [ABSTRACT FROM AUTHOR]