title: Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors.
abstract: A high throughput screening (HTS) hit, 1 (Plk1 K(i)=2.2 μM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K(i)=5 nM; EC(50)=1.05 μM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.
authors.affiliation: Medicinal Chemistry Technologies and Structural Biology, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. henry.zhang@abbott.com
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Xia
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mitten
authors.forename: Loren M
authors.initials: LM
authors.lastname: Lasko
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Stevan W
authors.initials: SW
authors.lastname: Djuric
authors.forename: Anil
authors.initials: A
authors.lastname: Vasudevan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1