Resistance gene-guided genome mining reveals the roseopurpurins as inhibitors of cyclin-dependent kinases.

Autor: Dunbar KL; Hexagon Bio, Menlo Park, CA 94025., Perlatti B; Hexagon Bio, Menlo Park, CA 94025., Liu N; Hexagon Bio, Menlo Park, CA 94025., Cornelius A; Hexagon Bio, Menlo Park, CA 94025., Mummau D; Hexagon Bio, Menlo Park, CA 94025., Chiang YM; Hexagon Bio, Menlo Park, CA 94025., Hon L; Hexagon Bio, Menlo Park, CA 94025., Nimavat M; Hexagon Bio, Menlo Park, CA 94025., Pallas J; Hexagon Bio, Menlo Park, CA 94025., Kordes S; Proteros Biostructures GmbH, Planegg D-82152, Germany., Ng HL; Hexagon Bio, Menlo Park, CA 94025., Harvey CJB; Hexagon Bio, Menlo Park, CA 94025.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Nov 28; Vol. 120 (48), pp. e2310522120. Date of Electronic Publication: 2023 Nov 20.
DOI: 10.1073/pnas.2310522120
Abstrakt: With the significant increase in the availability of microbial genome sequences in recent years, resistance gene-guided genome mining has emerged as a powerful approach for identifying natural products with specific bioactivities. Here, we present the use of this approach to reveal the roseopurpurins as potent inhibitors of cyclin-dependent kinases (CDKs), a class of cell cycle regulators implicated in multiple cancers. We identified a biosynthetic gene cluster (BGC) with a putative resistance gene with homology to human CDK2. Using targeted gene disruption and transcription factor overexpression in Aspergillus uvarum , and heterologous expression of the BGC in Aspergillus nidulans, we demonstrated that roseopurpurin C ( 1 ) is produced by this cluster and characterized its biosynthesis. We determined the potency, specificity, and mechanism of action of 1 as well as multiple intermediates and shunt products produced from the BGC. We show that 1 inhibits human CDK2 with a K iapp of 44 nM, demonstrates selectivity for clinically relevant members of the CDK family, and induces G1 cell cycle arrest in HCT116 cells. Structural analysis of 1 complexed with CDK2 revealed the molecular basis of ATP-competitive inhibition.
Competing Interests: Competing interests statement:K.L.D, B.P., N.L., D.M., A.C., Y.-M.C., L.H., M.N., J.P., H.L.N. and C.J.B.H. are all shareholders in Hexagon Bio.
Databáze: MEDLINE
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