500596-03-2Relevant articles and documents
Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A
Patrone, James D.,Pelz, Nicholas F.,Bates, Brittney S.,Souza-Fagundes, Elaine M.,Vangamudi, Bhavatarini,Camper, Demarco V.,Kuznetsov, Alexey G.,Browning, Carrie F.,Feldkamp, Michael D.,Frank, Andreas O.,Gilston, Benjamin A.,Olejniczak, Edward T.,Rossanese, Olivia W.,Waterson, Alex G.,Chazin, Walter J.,Fesik, Stephen W.
, p. 893 - 899 (2016)
Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that initiates the DNA damage response pathway through protein-protein interactions (PPIs) mediated by its 70N domain. The identification and use of chemical probes that can specifically disrupt these interactions is important for validating RPA as a cancer target. A high-throughput screen (HTS) to identify new chemical entities was conducted, and 90 hit compounds were identified. From these initial hits, an anthranilic acid based series was optimized by using a structure-guided iterative medicinal chemistry approach to yield a cell-penetrant compound that binds to RPA70N with an affinity of 812 nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is capable of inhibiting PPIs mediated by this domain.
COMPOUNDS
-
Page/Page column 99-100; 170, (2020/06/10)
The present invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, wherein: the group X-Y is -NHSO2- or -SO2NH-; R1 is H or alkyl; R2 is selected from COOH and a tetrazolyl group; R3 is selected from H, Cl and alkyl; R4 is selected from H, Cl and F; R5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R6 is H; R7 is selected from H, CN, haloalkyl, Cl, F, SO2-alkyl, SO2NR13R14, optionally substituted heteroaryl and alkyl; R8 is selected from H, alkyl, haloalkyl and halo; R9 is H, C1-C3-alkyl, or halo; R10 and R11, together with the nitrogen to which they are attached, form an azepanyl group, wherein (a) said azepanyl group is substituted by one or more substituents, or (b) one or two carbons in said azepanyl group are replaced by a group selected from O, NH, S and CO, and said azepanyl group is optionally further substituted; or R10 and R11, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl or piperidinyl group wherein (a) said azetidinyl, pyrrolidinyl or piperidinyl group is substituted by one or more substituents, or (b) one or two carbons in said azetidinyl, pyrrolidinyl or piperidinyl group are replaced by a group selected from NH, S and CO; or R10 and R11, together with the nitrogen to which they are attached, form an 8, 9 or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbons in the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic heterocycloalkyl group is optionally substituted; or R10 and R11, together with the nitrogen to which they are attached, form a 6 to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic group is optionally substituted, or said bicyclic group is optionally fused to a 5 or 6-membered aryl or heteroaryl group; R13 and R14 are each independently H or alkyl. Further aspects of the invention relate to such compounds for use in the field of immune-oncology and related applications.
Small Molecule Microarray Based Discovery of PARP14 Inhibitors
Peng, Bo,Thorsell, Ann-Gerd,Karlberg, Tobias,Schüler, Herwig,Yao, Shao Q.
supporting information, p. 248 - 253 (2016/12/30)
Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure–activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.
