2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19.
We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1(SER727) phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Aurélie
A
Mallinger
Merck KGaA, Darmstadt 64293, Germany.
Kai
K
Schiemann
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Christian
C
Rink
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Jimmy
J
Sejberg
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Mark A
MA
Honey
Merck KGaA, Darmstadt 64293, Germany.
Paul
P
Czodrowski
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Mark
M
Stubbs
Merck KGaA, Darmstadt 64293, Germany.
Oliver
O
Poeschke
Merck KGaA, Darmstadt 64293, Germany.
Michael
M
Busch
Merck KGaA, Darmstadt 64293, Germany.
Richard
R
Schneider
Merck KGaA, Darmstadt 64293, Germany.
Daniel
D
Schwarz
Merck KGaA, Darmstadt 64293, Germany.
Djordje
D
Musil
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Rosemary
R
Burke
Merck KGaA, Darmstadt 64293, Germany.
Klaus
K
Urbahns
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Paul
P
Workman
Merck KGaA, Darmstadt 64293, Germany.
Dirk
D
Wienke
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Paul A
PA
Clarke
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Florence I
FI
Raynaud
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Suzanne A
SA
Eccles
Merck KGaA, Darmstadt 64293, Germany.
Christina
C
Esdar
Merck KGaA, Darmstadt 64293, Germany.
Felix
F
Rohdich
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
Julian
J
Blagg
CDK19; CDK8; aldehyde oxidase; kinase inhibitor; mediator complex