A very long-acting parp inhibitor suppresses cancer cell growth in DNA repair-deficient tumor models was written by Fontaine, Shaun D.;Ashley, Gary W.;Houghton, Peter J.;Kurmasheva, Raushan T.;Diolaiti, Morgan;Ashworth, Alan;Peer, Cody J.;Nguyen, Ryan;Figg, William D. Sr.;Beckford-Vera, Denis R.;Santi, Daniel V.. And the article was included in Cancer Research in 2021.Category: ethers-buliding-blocks The following contents are mentioned in the article:
PARP inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromol. prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG40kDa carrier via a β-eliminative releasable linker. A single injection of the PEG~TLZ conjugate was as effective as ~30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms′′ tumor with a PALB2 mutation, the BRCA1-deficient MX-1 triple-neg. breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. Although the half-life of PEG~TLZ and released TLZ in the mouse was only ~1 day, the exposure of released TLZ from a single safe, ED of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG~TLZ in the MX-1 BRCA1-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long t1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG~TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated. This study involved multiple reactions and reactants, such as 2-Methoxyethylamine (cas: 109-85-3Category: ethers-buliding-blocks).
2-Methoxyethylamine (cas: 109-85-3) belongs to ethers. Esters perform as high-grade solvents for a broad array of plastics, plasticizers, resins, and lacquers, and are one of the largest classes of synthetic lubricants on the commercial market. Esters contain a carbonyl center, which gives rise to 120° C–C–O and O–C–O angles. Unlike amides, esters are structurally flexible functional groups because rotation about the C–O–C bonds has a low barrier. Their flexibility and low polarity is manifested in their physical properties; they tend to be less rigid (lower melting point) and more volatile (lower boiling point) than the corresponding amides. Category: ethers-buliding-blocks
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem