Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in 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).
The putA GEne Product: Two Enzymatic Activities and a Regulatory Function in a Single Polypeptide
James F. Kane in 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.
Future Therapy of Interstitial Lung Diseases
Lourdes R. Laraya-Cuasay, Walter T. Hughes in Interstitial Lung Diseases in Children, 2019
Proline analogues have shown to be effective in inhibiting collagen accumulation in several models of fibrosis.17 There have been several studies showing proline analogues prevent collagen accumulation in experimental pulmonary fibrosis. Using a rat oxygen toxicity model, Riley and associates showed that cw-hydroxyproline, L-azetidine-2-carboxylic acid, and L-3,4-dehydroproline were effective in preventing lung collagen accumulation.18,19 Collagen accumulation in bleomycin-induced fibrosis in rodents was shown to be prevented by ds-hydroxyproline20 and L-3,4-dehydroproline.21 In addition to the biochemical changes, administration of these agents partially prevented the decreased lung volume found in fibrosis.20,21 There were no overt toxic effects identified during the 2- to 4-week treatment periods, but the toxic effects of longer treatment periods have not been studied. These animal experiments suggest that short-term treatment with proline analogues is effective in preventing rapid accumulation of lung collagen in doses which do not cause overt toxicity.
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.
Selective COX-2 inhibitors as anticancer agents: a patent review (2014-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Sayyed Mohammad Ismail Mahboubi Rabbani, Afshin Zarghi
Pirahmadi et al. synthesized and assayed the effects of a new derivative of β-lactam structured ‘azetidine’ (compound (5), (Figure 8)) as an anticancer agent. They designed this analog based on the structure-activity relationship of selective COX-2 inhibitors [58].
Advances and challenges in drug design against tuberculosis: application of in silico approaches
Published in Expert Opinion on Drug Discovery, 2019
Alexey Aleksandrov, Hannu Myllykallio
Saxena et al. [60] used docking techniques to identify inhibitors of AlaDH enzyme. It was observed that this enzyme is overexpressed under hypoxic and nutrient starvation conditions in Mtb, which was further linked to the generation of alanine for peptidoglycan biosynthesis and the maintenance of the NAD+ pool under conditions when the terminal electron acceptor oxygen become limiting [61]. For the screening, Saxena et al. [60] defined the binding site by a protein region surrounding the NADH ligand in the X-ray structure. In the initial screening, pharmacophore modeling was used to preselect ligands that are likely to bind to AlaDH from the commercial Asinex library containing 500,000 compounds [62]. The pharmacophore sites were generated with the Phase module [12] and selected based on Glide XP energies computed with the NADH ligand for the pharmacophore model. Using this model, molecules from the database were docked and ranked. Around 100 compounds with best docking and Glide scores were then subjected to Glide XP and GOLD molecular docking. In addition to the docking scores, a final short listing of possible lead compounds was based on visual inspection of ligand interactions with the residues that are in the vicinity or constitute the NADH binding pocket. The in vitro inhibitory activity IC50 of the five shortlisted ligands was measured to be in the range of 35–80 µM showing that all hits were moderate inhibitors of Mtb l-AlaDH. In a different study [63], the authors employed the same protocol but using a structure of Mtb l-AlaDH in complex with a different substrate. Among the identified compounds, four displayed IC50 values ranging from 0.58 to 1.74 μM against Mtb L-AlaDH. The compounds also showed antituberculosis activity against Mtb with the lowest MIC of 1.53 μM. Interestingly, IC50 and MIC values for thirty compounds experimentally tested showed little correlation. More recently, Reshma et al. [64] applied the same protocol using the crystal structure of the Mtb L-AlaDH with bound cofactor NAD+. Based on this crystal structure they identified azetidine-2,4-dicarboxamide derivative as one of the potent inhibitors with IC50 of 9.22 µM. Subsequent lead optimization by synthesis led to the discovery of a substituted compound with IC50 against L-AlaDH of 3.83 µM. This compound demonstrated MIC of 11.81 µM against Mtb H37Rv.
Related Knowledge Centers
- Organic Compound
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