title: Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.
abstract: Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine25was also shown to have high potency against the CDK9 enzyme (3 nM).
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Carl S
authors.initials: CS
authors.lastname: Rye
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Nicola E A
authors.initials: NE
authors.lastname: Chessum
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Lamont
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Pike
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Faulder
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Demeritt
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Kemmitt
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Tucker
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Zani
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cheeseman
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: Isaac
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Goodwin
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Boros
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Henley
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: de Billy
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lynch
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Robert
authors.initials: R
authors.lastname: Te Poele
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Lisa O'
authors.initials: LO
authors.lastname: Fee
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Foote
authors.affiliation: AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
authors.forename: Keith
authors.initials: K
authors.lastname: Jones