4ZZ1

HUMAN GAR TRANSFORMYLASE IN COMPLEX WITH GAR AND (S)-2-({4-[3-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-6-YL)-PROPYL]-THIOPHENE-2-CARBONYL}-AMINO)-PENTANEDIOIC ACID

Summary for 4ZZ1

• Entry DOI: 10.2210/pdb4zz1/pdb
• Related: 1MEJ 1MEN 1MEO 1NJS 1RBM 1RBQ 1RBY 1RBZ 1RC0 1RC1 1ZLX 1ZLY 4EW2 4EW3 4ZYT 4ZYU 4ZYV 4ZYW 4ZYX 4ZYY 4ZYZ 4ZZ0 4ZZ2 4ZZ3
• Descriptor: Trifunctional purine biosynthetic protein adenosine-3, GLYCINAMIDE RIBONUCLEOTIDE, (S)-2-({4-[3-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-propyl]-thiophene-2-carbonyl}-amino)-pentanedioic acid, ... (4 entities in total)
• Functional Keywords: gar transformylase, antifolate, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 23541.76

Authors

Deis, S.M.,Dann III, C.E. (deposition date: 2015-05-22, release date: 2015-12-16, Last modification date: 2023-09-27)

Primary citation

Wang, L.,Wallace, A.,Raghavan, S.,Deis, S.M.,Wilson, M.R.,Yang, S.,Polin, L.,White, K.,Kushner, J.,Orr, S.,George, C.,O'Connor, C.,Hou, Z.,Mitchell-Ryan, S.,Dann, C.E.,Matherly, L.H.,Gangjee, A.
6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor alpha and the Proton-Coupled Folate Transporter in Human Tumors.
J.Med.Chem., 58:6938-6959, 2015

PubMed Abstract: 2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine antifolate thiophene regioisomers of AGF94 (4) with a thienoyl side chain and three-carbon bridge lengths [AGF150 (5) and AGF154 (7)] were synthesized as potential antitumor agents. These analogues inhibited proliferation of Chinese hamster ovary (CHO) sublines expressing folate receptors (FRs) α or β (IC50s < 1 nM) or the proton-coupled folate transporter (PCFT) (IC50 < 7 nM). Compounds 5 and 7 inhibited KB, IGROV1, and SKOV3 human tumor cells at subnanomolar concentrations, reflecting both FRα and PCFT uptake. AGF152 (6) and AGF163 (8), 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine thiophene regioisomers, also inhibited growth of FR-expressing CHO and KB cells. All four analogues inhibited glycinamide ribonucleotide formyltransferase (GARFTase). Crystal structures of human GARFTase complexed with 5 and 7 were reported. In severe combined immunodeficient mice bearing SKOV3 tumors, 7 was efficacious. The selectivity of these compounds for PCFT and for FRα and β over the ubiquitously expressed reduced folate carrier is a paradigm for selective tumor targeting.

PubMed: 26317331
DOI: 10.1021/acs.jmedchem.5b00801

Experimental method

X-RAY DIFFRACTION (1.351 Å)