Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines as highly potent EGFR-TK inhibitors with Src-family activity.
The epidermal growth factor receptor is an important target in molecular cancer therapy. Herein, the enzymatic inhibition potential of a series of chiral and non chiral pyrrolopyrimidine based derivatives have been investigated and optimised. Overall, seven new compounds were identified having enzymatic IC50 values comparable to or better than the commercial drug Erlotinib. High activity was also confirmed towards the epidermal growth factor receptor L858R and L861Q mutants. Based on calculated druglike properties, eight compounds were further evaluated towards a panel of 52 other kinases revealing interesting Src-family kinase and colony stimulating factor 1 receptor kinase inhibitory activity. Cell proliferation studies with the cell lines A431, C-33A, AU-565, K-562 and genetically engineered Ba/F3-EGFR(L858R) cells also showed several molecules to be more active than Erlotinib, and thus confirming these pyrrolopyrimidines as attractive drug candidates or lead structures.
Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Svein.jacob.kaspersen@chem.ntnu.no.
Svein Jacob
SJ
Kaspersen
Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway; Sør-Trøndelag University College, E.C. Dahls gt. 2, NO-7004 Trondheim, Norway. Electronic address: Jin.han@chem.ntnu.no.
Jin
J
Han
Norwegian University of Science and Technology, Department of Cancer Research and Molecular Medicine, Prinsesse Kristinas gt. 1, NO-7006 Trondheim, Norway. Electronic address: kristin.norsett@ntnu.no.
Kristin G
KG
Nørsett
Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: line.rydsa@sintef.no.
Line
L
Rydså
Sør-Trøndelag University College, Erling Skjalgssons gt. 1, NO-7004 Trondheim, Norway. Electronic address: eli.kjobli@hist.no.
Eli
E
Kjøbli
Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: steffen.bugge@chem.ntnu.no.
Steffen
S
Bugge
Norwegian University of Science and Technology, Department of Cancer Research and Molecular Medicine, Prinsesse Kristinas gt. 1, NO-7006 Trondheim, Norway; Sør-Trøndelag University College, Erling Skjalgssons gt. 1, NO-7004 Trondheim, Norway. Electronic address: geir.bjorkoy@hist.no.
Geir
G
Bjørkøy
Sør-Trøndelag University College, E.C. Dahls gt. 2, NO-7004 Trondheim, Norway. Electronic address: Eirik.Sundby@hist.no.
Eirik
E
Sundby
Norwegian University of Science and Technology, Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: bard.helge.hoff@chem.ntnu.no.
Bård Helge
BH
Hoff
D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000378:metabolism*
D000588:Amines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D066246:ErbB Receptors; D019061:src-Family Kinases
1-Phenylethanamin (PubChem CID: 7408); 2-Amino-2-phenylethan-1-ol (PubChem CID: 92466); 2-Methoxyphenylboronic acid (PubChem CID: 2733958); 4-(Hydroxymethyl)phenylboronic acid (PubChem CID: 2734706); Benzylamine (PubChem CID: 7504); CSF1R kinase; Cancer; EGFR-TK; Erlotinib; Erlotinib (PubChem CID: 176870); PKI-166 (PubChem CID: 6918403); Pyrrolopyrimidine; Src-kinase