Abstract：
:The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Guo Z,Sevrioukova IF,Denisov IG,Zhang X,Chiu TL,Thomas DG,Hanse EA,Cuellar RAD,Grinkova YV,Langenfeld VW,Swedien DS,Stamschror JD,Alvarez J,Luna F,Galván A,Bae YK,Wulfkuhle JD,Gallagher RI,Petricoin EF Rd,Norris B,doi
10.1016/j.chembiol.2017.08.009subject
Has Abstractpub_date
2017-10-19 00:00:00pages
1259-1275.e6issue
10eissn
2451-9456issn
2451-9448pii
S2451-9456(17)30283-0journal_volume
24pub_type
杂志文章abstract：:Recent advances in induced pluripotent stem cell technologies and phenotypic screening shape the future of bioactive small-molecule discovery. In this review we analyze the impact of small-molecule phenotypic screens on drug discovery as well as on the investigation of human development and disease biology. We further...
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