Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Bigi-Botterill, Simone V.¹  Ivetac, Anthony²  Bradshaw, Erica L.³  Cole, Derek¹  Dougan, Douglas R.⁴  Ermolieff, Jacques¹  Halkowycz, Petro¹  Johnson, Ben⁵  McBride, Christopher⁶  Pickens, Jason¹  Sabat, Mark¹  Swann, Steven⁷ 

[1] Takeda Res Calif, Gastroenterol Drug Discovery Unit, Med Chem & In Vitro Pharmacol, 9625 Towne Ctr Dr, San Diego, CA 92121 USA

[2] Mirati Therapeut, 9393 Towne Ctr Dr 200, San Diego, CA 92121 USA

[3] Takeda Res Calif, Quantitat Translat Sci, 9625 Towne Ctr Dr, San Diego, CA 92121 USA

[4] Takeda Res Calif, Gastroenterol Drug Discovery Unit, Struct Biol & Biophys, 9625 Towne Ctr Dr, San Diego, CA 92121 USA

[5] Takeda Res Calif, Neurosci Drug Discovery Unit, Med Chem, 9625 Towne Ctr Dr, San Diego, CA 92121 USA

[6] 858 Therapeut, 4757 Nexus Ctr Dr 150, San Diego, CA 92121 USA

[7] Silicon Therapeut, Chem & Design, 451 D St 205, Boston, MA 02210 USA

关键词: Mitogen-Activated Protein Kinase Kinase;    Kinase (MAP3K);    Apoptosis Signal-Regulating Kinase-1 (ASK1);    Structure-Based Drug Design (SBDD);    Cardiac injury;    Kinome selectivity;   

DOI  :  10.1016/j.bmcl.2020.127405

来源: Elsevier

【 摘 要 】

Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38-and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and K-d < 1 nM. Of the 350 kinases tested, 10 has an IC50 <= 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in 1% of the 5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.

【 授权许可】

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