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1.
Molecules ; 27(12)2022 Jun 11.
Article in English | MEDLINE | ID: mdl-35744895

ABSTRACT

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.


Subject(s)
Bile Duct Neoplasms , Bone Neoplasms , Chondrosarcoma , Glioma , Leukemia, Myeloid, Acute , Animals , Bile Ducts, Intrahepatic , Chondrosarcoma/diagnostic imaging , Chondrosarcoma/genetics , Glioma/diagnostic imaging , Glioma/genetics , Humans , Mice , Mutation , Positron-Emission Tomography , Pyridines , Quinolines , Tomography, Emission-Computed, Single-Photon
2.
Nat Protoc ; 16(11): 5250-5273, 2021 11.
Article in English | MEDLINE | ID: mdl-34707256

ABSTRACT

The free-state solution behaviors of drugs profoundly affect their properties. Therefore, it is critical to properly evaluate a drug's unique multiphase equilibrium when in an aqueous enviroment, which can comprise lone molecules, self-associating aggregate states and solid phases. To date, the full range of nano-entities that drugs can adopt has been a largely unexplored phenomenon. This protocol describes how to monitor the solution behavior of drugs, revealing the nano-entities formed as a result of self-associations. The procedure begins with a simple NMR 1H assay, and depending on the observations, subsequent NMR dilution, NMR T2-CPMG (spin-spin relaxation Carr-Purcell-Meiboom-Gill) and NMR detergent assays are used to distinguish between the existence of fast-tumbling lone drug molecules, small drug aggregates and slow-tumbling colloids. Three orthogonal techniques (dynamic light scattering, transmission electron microscopy and confocal laser scanning microscopy) are also described that can be used to further characterize any large colloids. The protocol can take a non-specialist between minutes to a few hours; thus, libraries of compounds can be evaluated within days.


Subject(s)
Nanostructures/chemistry , Pharmaceutical Preparations/chemistry , Magnetic Resonance Spectroscopy
3.
Adv Ther ; 36(6): 1480-1484, 2019 06.
Article in English | MEDLINE | ID: mdl-30980281

ABSTRACT

KRAS (Kirsten rat sarcoma viral oncogene) or BRAF (v-raf murine sarcoma viral oncogene homolog B1) constitutive activation leads to anti-EGFR (epidermal growth factor receptor) therapy resistance of metastatic colorectal cancer patients. In this article we investigate the effects of anti-MEK (mitogen-activated protein kinase) antibody (trametinib) combined with anti-EGFR (cetuximab) on colon cancer cell lines with different RAS statuses. Even though cetuximab has no effect on RAS cell viability and ERK (extracellular-signal-regulated kinase) phosphorylation (one of the last kinases of the EGFR pathway), trametinib can induce cell death and inhibit the activation of ERK alone or in combination with cetuximab. In a more pathologic context, we observed that KRAS colon cancer patient biopsies treated ex vivo with trametinib and cetuximab also present less ERK phosphorylation. Finally, nine ovarian, endometrial and colon cancer patients with different KRAS statuses were treated with anti-EGFR/anti-MEK combination off label after molecular tumor board decision. KRAS exon 2 patients have significantly longer PFS (progression-free survival) than with previous lines of treatments. We believe that such observations provide a rationale for designing a clinical trial to test this association in RAS exon 2 mutated cancers.


Subject(s)
Cetuximab/therapeutic use , Colorectal Neoplasms/drug therapy , ErbB Receptors/antagonists & inhibitors , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/drug effects , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Adult , Aged , Aged, 80 and over , Animals , Antineoplastic Agents/therapeutic use , Female , Humans , Male , Mice , Middle Aged , Neoplasm Metastasis/drug therapy , Rats
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