PMID- 26918392 OWN - NLM STAT- MEDLINE DCOM- 20171229 LR - 20211204 IS - 1473-5741 (Electronic) IS - 0959-4973 (Print) IS - 0959-4973 (Linking) VI - 27 IP - 6 DP - 2016 Jul TI - RES-529: a PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes. PG - 475-87 LID - 10.1097/CAD.0000000000000354 [doi] AB - RES-529 (previously named Palomid 529, P529) is a phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway inhibitor that interferes with the pathway through both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) dissociation. This compound is currently being developed in oncology and ophthalmology. The oncology focus is for the treatment of glioblastoma, where it has received orphan designation by the US Food and Drug Administration, and prostate cancer. We present a review of the PI3K/AKT/mTOR pathway, its role in tumorigenesis, and the potential of RES-529 in cancer treatment. RES-529 inhibits mTORC1/mTORC2 activity in various cancer cell lines, as noted by decreased phosphorylation of substrates including ribosomal protein S6, 4E-BP1, and AKT, leading to cell growth inhibition and death, with activity generally in the range of 5-15 mumol/l. In animal tumor models where the PI3K/AKT/mTOR pathway is abnormally activated (i.e. glioblastoma, prostate cancer, and breast cancer), RES-529 reduces tumor growth by as much as 78%. RES-529 treatment is synergistic with radiation therapy, chemotherapy, and hormonal therapy in reducing tumor growth, potentially by preventing PI3K/AKT/mTOR pathway activation associated with these treatments. Furthermore, this compound has shown antiangiogenic activity in several animal models. mTORC1 and mTORC2 have redundant and distinct activities that contribute toward oncogenesis. Current inhibitors of this pathway have primarily targeted mTORC1, but have shown limited clinical efficacy. Inhibitors of mTORC1 and mTORC2 such as RES-529 may therefore have the potential to overcome the deficiencies found in targeting only mTORC1. FAU - Weinberg, Mark A AU - Weinberg MA AD - RestorGenex Corporation, Buffalo Grove, Illinois, USA. LA - eng PT - Journal Article PT - Review PL - England TA - Anticancer Drugs JT - Anti-cancer drugs JID - 9100823 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antineoplastic Agents) RN - 0 (Benzopyrans) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - XV9409EWG4 (palomid 529) SB - IM MH - Angiogenesis Inhibitors/pharmacology MH - Animals MH - Antineoplastic Agents/*pharmacology MH - Benzopyrans/*pharmacology MH - Brain Neoplasms/drug therapy/metabolism MH - Glioblastoma/drug therapy/metabolism MH - Humans MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - Mechanistic Target of Rapamycin Complex 2/*metabolism MH - Metabolic Networks and Pathways/drug effects MH - Molecular Targeted Therapy/methods MH - Neoplasms/drug therapy/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC4881730 EDAT- 2016/02/27 06:00 MHDA- 2017/12/30 06:00 PMCR- 2016/05/26 CRDT- 2016/02/27 06:00 PHST- 2016/02/27 06:00 [entrez] PHST- 2016/02/27 06:00 [pubmed] PHST- 2017/12/30 06:00 [medline] PHST- 2016/05/26 00:00 [pmc-release] AID - 10.1097/CAD.0000000000000354 [doi] PST - ppublish SO - Anticancer Drugs. 2016 Jul;27(6):475-87. doi: 10.1097/CAD.0000000000000354.