An inhibitor of oxidative phosphorylation exploits cancer vulnerability.
Jennifer R MolinaYuting SunMarina ProtopopovaSonal GeraMadhavi BandiChristopher BristowTimothy McAfoosPietro MorlacchiJeffrey J AckroydAhmed-Noor A AgipGheath Al-AtrashJohn AsaraJennifer BardenhagenCaroline C CarrilloChristopher CarrollEdward ChangStefan CiureaJason B CrossBarbara CzakoAngela DeemNaval DaverJohn Frederick de GrootJian-Wen DongNingping FengGuang GaoJason GayMary Geck DoJennifer GreerVirginia GiulianiJing HanLina HanVerlene K HenryJudy HirstSha HuangYongying JiangZhijun KangTin KhorSergej KonoplevYu-Hsi LinGang LiuAlessia LodiTimothy LoftonHelen MaMikhila MahendraPolina MatreRobert MullinaxMichael PeoplesAlessia PetrocchiJaime Rodriguez-CanaleRiccardo SerreliThomas ShiMelinda SmithYoko TabeJay TheroffStefano TizianiQuanyun XuQi ZhangFlorian L MullerRonald A DePinhoCarlo ToniattiGiulio F DraettaTimothy P HeffernanMarina KonoplevaPhilip JonesM Emilia Di FrancescoJoseph R MarszalekPublished in: Nature medicine (2018)
Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.
Keyphrases
- acute myeloid leukemia
- small molecule
- papillary thyroid
- induced apoptosis
- oxidative stress
- clinical trial
- squamous cell
- allogeneic hematopoietic stem cell transplantation
- signaling pathway
- endoplasmic reticulum stress
- white matter
- acute lymphoblastic leukemia
- lymph node metastasis
- climate change
- high throughput
- randomized controlled trial
- resting state
- multiple sclerosis
- quality improvement
- combination therapy
- young adults
- squamous cell carcinoma
- open label
- protein protein
- blood brain barrier
- solar cells