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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Cobimetinib (CotellicTM) (Figure 6.51) is a MEK inhibitor developed by Exelixis and Genentech (Roche). It is used in combination with the B-RAF inhibitor vemurafenib (ZelborafTM) to treat melanoma. The structure is unusual in containing a four-membered azetidine ring and four halogen atoms. Structure of cobimetinib (CotellicTM).
Developmental Aspects of the Alveolar Epithelium and the Pulmonary Surfactant System
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
Jacques R. Bourbon, Caroline Fraslon
Experiments have been undertaken in order to disturb the formation of the basement membrane in developing lung in vivo or in in vitro models of lung organogenesis and to evaluate the consequences on epithelial differentiation and maturation. One approach consisted of perturbing collagen synthesis with the aid of amino acid analogs of proline, an amino acid particularly abundant in collagen. In vitro, l-azetidine-2-carboxylic acid (LACA) and α,α′-dipyridyl deeply perturbed branching morphogenesis of mouse lung rudiments, although cell and tissue integrity was not affected.97 The administration of LACA to rat fetuses retarded lung growth and surfactant biosynthesis.98 This result, however, must be interpreted with caution. The delay in surfactant synthesis could effectively be a consequence of impairment of ECM biosynthesis and alteration of the modulation of epithelial maturation by the basement membrane. However, it can also result from impairments in the production of various proline-containing proteins other than collagens, including a number of enzymes and surfactant protein A (SP-A), which is known to contain a collagen-like domain (see Chapter 4).
The putA GEne Product: Two Enzymatic Activities and a Regulatory Function in a Single Polypeptide
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
Mutations that affect the enzyme activities of the putA gene product show two phenotypes with respect to the regulation of the putP gene. Wild type cells are sensitive to the proline analogue azetidine carboxylic acid (AZTS). Mutants defective for the putP gene are resistant to AZT. Mutants constitutive for both the expression of proline oxidase and proline permease show a heightened sensitivity to AZT (AZTSS phenotype).12 Mutants lacking proline oxidase activity may be either sensitive to AZT at a level similar to that of wild type cells (AZTS) or demonstrate a heightened sensitivity (AZTSS) similar to that of mutants constitutive for the expression of the put genes. The putA− mutants which are AZTSS were shown to have lost their ability to regulate the permease.12 They behave like constitutive mutants for the putP gene. All insertion and amber mutants in the putA gene are in the AZTSS class.
Selective estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs): a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2022
James S. Scott, Bernard Barlaam
A patent focussed on the in vitro antiproliferation activity of OP-1074 48 in combination with various chemotherapeutic agents was published by Olema pharmaceuticals in collaboration with Pfizer (Figure 20)[116]. A subsequent medicinal chemistry publication detailed the pharmacology of the compound (IC50 3.2 nM) and demonstrated regression in an MCF-7 xenograft model when dosed orally at 100 mg/kg[117]. In addition, a structural biology investigation as to how subtle changes in structure led to different pharmacology implicated the dynamics of helix 12 of the protein as a key component. A subsequent filing from the same inventors but attributed to Pfizer, detailed 20 related compounds with a cyclic azetidine base[118]. Example 105 49 was reported as a potent degrader of the estrogen receptor (IC50 4 nM). In 2017, a patent containing two compounds was reported with overlapping inventors but attributed to Olema pharmaceuticals[119]. Example B 50 was reported as a potent degrader of the estrogen receptor (IC50 2.8 nM) with in vivo activity at 10 mg/kg in an MCF-7 xenograft model. Comparative data with closely related chemical equity from the Genentech filing (Examples 102 and 107) was included to highlight differences in human protein binding and murine exposure. A more recent patent application [120] focussed on this compound with data showing good exposure in mouse, rat, dog, and monkey. Additional data relating to exposure in brain and in vivo activity as both single agent (1–10 mg/kg) and in combination with palbociclib were included. Olema have a compound (OP-1250) currently in development and, whilst the structure has not been formally disclosed at the time of writing, 50 is undoubtedly a compound of significant interest.
Monocyclic beta–lactams for therapeutic uses: a patent overview (2010–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Katarina Grabrijan, Nika Strašek, Stanislav Gobec
Unlike other beta-lactams, monocyclic beta-lactams are produced by chemical synthesis rather than by fermentation. There is a continuous development of synthetic approaches to produce differently substituted 2-azetidines. The Staudinger ketene-imine reaction is still the most common method [6,7]. Besides their role as biologically active molecules, monocyclic beta-lactams are widely used as synthetic intermediates and chiral synthons in the synthesis of other biologically active molecules. In addition, they are precursors in the highly efficient semi-synthesis of paclitaxel and docetaxel [8].
Enhancement of tumor immunogenicity by the introduction of non- proteinogenic amino acid azetidine-2-carboxylic acid
Published in OncoImmunology, 2022
Siyu Li, Shiqing Wang, Baorui Tian, Na Li, Yanan Chen, Yanhua Liu, Weijun Su, Yan Fan, Yongjun Piao, Jia Li, Longlong Wang, Jin Zhao, Shu Wang, Yi Shi, Rong Xiang
Tumor-specific antigens are usually generated by mutations in genomic DNA.1 However, mutated proteins can also be produced by translation errors in protein biosynthesis.13 Although the translation fidelity is maintained by multiple protein quality control mechanisms including the proofreading function of the aminoacyl-tRNA synthetases (aaRSs), which ligate amino acids to their specific tRNAs and selectively remove non-cognate amino acids from mischarged tRNAs,13,14 the protein mistranslation events occur due to the existence of some vegetable-sourced analogues of the 20 proteinogenic amino acids, which are too structurally similar to be distinguished by corresponding aaRSs.13–16 These near-cognate amino acids cause regional mistranslation, in which one proteinogenic amino acid is substituted for a near-cognate nonproteinogenic amino acid, regardless of the codon. The mistranslated proteins may not fold correctly and induce subsequent detrimental cellular responses.17,18 However, some studies show that protein mistranslation is beneficial to cells in certain circumstances.19–22 For example, mistranslation increases the diversity of cell surface proteins to expand the phenotypic variability under nutritional or immunological stress in candida albicans, escherichia coli, and mycobacteria, eventually improving the cell viability. Azetidine-2-carboxylic acid (Aze), a nonproteinogenic amino acid analog of proline (Figure 1A),23 can be activated by prolyl-tRNA synthetase and misincorporated into proline (Pro) positions of proteins in mammalian cells.15 The misincorporation of Aze has been proposed to be connected with the occurrence of some types of multiple sclerosis (MS) in both newborn lambs whose mothers were fed with Aze-rich food and in humans consuming large amounts of Aze-rich food such as sugar beets,24,25 which indicate that the misincorporation of Aze may influence the structure and function of proteins.