title: Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors.
abstract: Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound1bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound26is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC50of 3 μM after 6 h.
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Johannes
authors.affiliation: AstraZeneca R&D Cambridge Science Park , Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bates
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Carl
authors.initials: C
authors.lastname: Beigie
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Belmonte
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: John
authors.initials: J
authors.lastname: Breen
authors.affiliation: Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
authors.forename: Shenggen
authors.initials: S
authors.lastname: Cao
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Centrella
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Clark
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: John W
authors.initials: JW
authors.lastname: Cuozzo
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Christoph E
authors.initials: CE
authors.lastname: Dumelin
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Sevan
authors.initials: S
authors.lastname: Habeshian
authors.affiliation: AstraZeneca R&D Cambridge Science Park , Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Hargreaves
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Camil
authors.initials: C
authors.lastname: Joubran
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Kazmirski
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Keefe
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lamb
authors.affiliation: Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
authors.forename: Haiye
authors.initials: H
authors.lastname: Lan
authors.affiliation: Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Li
authors.affiliation: Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ma
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Mlynarski
authors.affiliation: AstraZeneca R&D Alderley Park , Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Packer
authors.affiliation: AstraZeneca R&D Cambridge Science Park , Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Rawlins
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Robbins
authors.affiliation: Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Shen
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sigel
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Holly H
authors.initials: HH
authors.lastname: Soutter
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Su
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Troast
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.affiliation: AstraZeneca R&D Cambridge Science Park , Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
authors.forename: Kate F
authors.initials: KF
authors.lastname: Wickson
authors.affiliation: Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
authors.forename: Chengyan
authors.initials: C
authors.lastname: Wu
authors.affiliation: X-Chem Pharmaceuticals , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Pharmaron Beijing Co., Ltd. 6 Taihe Road BDA, Beijing 100176 P. R. China.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Hird
keywords: Mcl-1; macrocycles; peptides; protein−protein interactions