title: "Addition" and "Subtraction": Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors.
abstract: While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them.
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Xin
authors.identifier: 0000-0002-0930-0750
authors.initials: X
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: John
authors.initials: J
authors.lastname: Giraldes
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sprague
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Subarna
authors.initials: S
authors.lastname: Shakya
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Zhuoliang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Carol
authors.initials: C
authors.lastname: Joud
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Christine Hiu-Tung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Straub
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Duca
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Kristen
authors.initials: K
authors.lastname: Hurov
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Shao
authors.affiliation: Novartis Institutes for BioMedical Research, Inc. , Cambridge, Massachusetts 02139, United States.
authors.forename: B Barry
authors.initials: BB
authors.lastname: Touré
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016350:Leucine Zippers; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases