title: Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.
abstract: A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States. Electronic address: ylou@nurix-inc.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Davis
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Han
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Junbae
authors.initials: J
authors.lastname: Hong
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Buelent
authors.initials: B
authors.lastname: Kocer
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Kondru
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Litman
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: McIntosh
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Keshab
authors.initials: K
authors.lastname: Sarma
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Judy
authors.initials: J
authors.lastname: Suh
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Taygerly
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 3431 Hillview Ave, Palo Alto, CA 94304, United States.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Owens
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D005461:Fluorine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: BTK; Bruton’s Tyrosine Kinase; Fluorine scan; Rational fluorine scan; Structure-based drug design