PDBsum entry 3cjo

Motor protein

PDB id: 3cjo

Contents

Protein chains

330 a.a.

Ligands

ADP ×2

K30 ×2

Metals

_MG ×2

Waters ×323

References listed in PDB file

Key reference

• Title: Kinesin spindle protein (ksp) inhibitors. 9. Discovery of (2s)-4-(2,5-Difluorophenyl)-N-[(3r,4s)-3-Fluoro-1-Methylpiperidin-4-Yl]-2-(Hydroxymethyl)-N-Methyl-2-Phenyl-2,5-Dihydro-1h-Pyrrole-1-Carboxamide (mk-0731) for the treatment of taxane-Refractory cancer.
• Authors: C.D.Cox, P.J.Coleman, M.J.Breslin, D.B.Whitman, R.M.Garbaccio, M.E.Fraley, C.A.Buser, E.S.Walsh, K.Hamilton, M.D.Schaber, R.B.Lobell, W.Tao, J.P.Davide, R.E.Diehl, M.T.Abrams, V.J.South, H.E.Huber, M.Torrent, T.Prueksaritanont, C.Li, D.E.Slaughter, E.Mahan, C.Fernandez-Metzler, Y.Yan, L.C.Kuo, N.E.Kohl, G.D.Hartman.
• Ref.: J Med Chem, 2008, 51, 4239-4252.
• PubMed id: 18578472

Abstract

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.