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Structure-activity studies revealed that amino substituted thalidomide had improved antitumor activity, which was due to its ability to directly inhibit both the tumor cell and vascular compartments of myeloma cancers. [18] This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo. [19]
The thalidomide molecule is a synthetic derivative of glutamic acid and consists of a glutarimide ring and a phthaloyl ring (Figure 5). [15] [16] Its IUPAC name is 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione and it has one chiral center [15] After thalidomide's selective inhibition of TNF-α had been reported, a renewed effort was put in thalidomide's clinical development.
Cereblon is a protein that in humans is encoded by the CRBN gene. [5] The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans. [5]
The generation of a protein sequence is much easier than the determination of a protein structure. However, the structure of a protein gives much more insight in the function of the protein than its sequence. Therefore, a number of methods for the computational prediction of protein structure from its sequence have been developed. [39]
Dimopoulos MA, Hungria VT, Radinoff A, Delimpasi S, Mikala G, Masszi T, et al. (October 2023). "Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study". The Lancet. Haematology.
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In October 2021, Oncopeptides AB announced the withdrawal of Pepaxto from the US market after the OCEAN trial's data showed no improvement in terms of overall survival versus pomalidomide in the ITT group (19.8 months in the melphalan flufenamide group versus 25.0 months in the pomalidomide group, HR 1.10, 95% CI 0.85–1.44, p = 0,47). [24] [25]
Swiss-model (stylized as SWISS-MODEL) is a structural bioinformatics web-server dedicated to homology modeling of 3D protein structures. [1] [2] As of 2024, homology modeling is the most accurate method to generate reliable three-dimensional protein structure models and is routinely used in many practical applications. Homology (or comparative ...