Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones.
The benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one core was discovered as a novel ERK5 (also known as MAPK7 and BMK1) inhibitor scaffold, previously. Further structure-activity relationship studies of this scaffold led to the discovery of ERK5-IN-1 (26) as the most selective and potent ERK5 inhibitor reported to date. 26 potently inhibits ERK5 biochemically with an IC₅₀ of 0.162 ± 0.006 μM and in cells with a cellular EC₅₀ for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 ± 0.03 μM. Furthermore, 26 displays excellent selectivity over other kinases with a KINOMEscan selectivity score (S₁₀) of 0.007, and exhibits exceptional bioavailability (F%) of 90% in mice. 26 will serve as a valuable tool compound to investigate the ERK5 signaling pathway and as a starting point for developing an ERK5 directed therapeutic agent.
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA 02115, USA.
Xianming
X
Deng
Jonathan M
JM
Elkins
Jinwei
J
Zhang
Qingkai
Q
Yang
Tatiana
T
Erazo
Nestor
N
Gomez
Hwan Geun
HG
Choi
Jinhua
J
Wang
Nicolas
N
Dzamko
Jiing-Dwan
JD
Lee
Taebo
T
Sim
NamDoo
N
Kim
Dario R
DR
Alessi
Jose M
JM
Lizcano
Stefan
S
Knapp
Nathanael S
NS
Gray
D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001381:Azepines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000591576:benzo(e)pyrimido-(5,4-b)diazepine-6(11H)-one; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D048054:Mitogen-Activated Protein Kinase 7
2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl; BMK1; Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one; DCAMKL2; DIEA; DMA; EGF; ERK5; ERK5 inhibitor; HCC; Kinase selectivity; LRRK2; MAP kinase kinase 5; MAPK; MEK5; N,N-diisopropylethylamine; N,N-dimethylacetamide; PLK; PML; Pd(2)(dba)(3); RSK; SAR; X-phos; XVBGRTMNFNMINE-UHFFFAOYSA-N; big MAP kinase 1; doublecortin and CaM kinase-like 2; epidermal growth factor; extracelluar-signal-regulated kinase 5; hepatocellular carcinoma; leucine rich repeat kinase 2; mitogen-activated protein kinase; mitogen-activated protein kinase 7; polo-like kinase; promyelocytic leukemia protein; ribosomal S6 kinase; structure–activity relationship; tris(dibenzylideneacetone)dipalladium-(0)