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.
Thermotolerance in Mammalian Systems: A Review
Leopold J. Anghileri, Jacques Robert in Hyperthermia In Cancer Treatment, 2019
The molecular mechanism(s) for the development of thermotolerance is not well understood, but the experimental evidence suggests that protein synthesis may play a role in its manifestation.6,42,43 In recent years it has been reported that heat or other environmental stresses induce the synthesis of a family of proteins, referred to as heat shock proteins (HSP), in a wide variety of cells varying from Drosophila to mammals.44,45 It has been suggested that the function of HSP may be related to thermotolerance.46–50Many investigators have performed experiments to determine the relationship between thermotolerance and HSP synthesis. So far, almost all results show a good temporal relationship between HSP synthesis and thermotolerance development in many different mammalian systems.45,49,50 Recently, Li has examined the quantitative relationship between cell survival and levels of HSP in thermotolerant cells (Figure 4), and has found that the amounts of high molecular weight HSP (70 kD, 87 kD, and 110 kD) correlate well with survival during the decay of thermotolerance.51 Furthermore, it has been shown that agents known to induce thermotolerance induce synthesis of HSP; conversely, agents known to induce synthesis of HSP (except amino acid analogues, e.g., canavanine) induce thermotolerance.53–55 The good temporal correlation between HSP synthesis and thermotolerance certainly suggests that there may be a causative relationship. Li and Laszlo have recently shown that incorporation of amino acid analogues, e.g., canavanine or azetidine, induce enhanced synthesis of HSP, but at the same time it sensitizes cells to subsequent heat challenge and inhibits the development of thermotolerance. The amino acid analogue data apparently suggest that HSP synthesized in the presence of canavanine may be defective or nonfunctional.56,57
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].
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].
Related Knowledge Centers
- Organic Compound
- Proline
- Nitrogen
- Saturated & Unsaturated Compounds
- Carbon
- Beta-Lactam
- Aluminium Chloride
- Azetidine-2-Carboxylic Acid
- Azete