Journal Article

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Garlich, Joseph R., Morales, Guillermo A., Andrews, Forest H., Singh, Alok R., Durden, Donald L., Kutateladze, Tatiana G., Smith, Cassandra A., Joshi, Shweta

2017

Overview

MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.

• Publisher: National Academy of Sciences
• Subject: Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Binding sites / Biochemistry / Biological Sciences / Cancer / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - enzymology / Carcinoma, Pancreatic Ductal - pathology / Carcinoma, Pancreatic Ductal - secondary / Cell Cycle Proteins / Cell growth / Cell Line, Tumor / Drug Screening Assays, Antitumor / Female / Humans / Kinases / Metastasis / Mice / Mice, Nude / Models, Molecular / Morpholines - pharmacology / Morpholines - therapeutic use / Neoplasm Metastasis - drug therapy / Neoplasm Metastasis - prevention & control / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - physiology / Neuroblastoma - drug therapy / Neuroblastoma - enzymology / Neuroblastoma - pathology / Neuroblastoma - secondary / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - chemistry / Nuclear Proteins - physiology / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - enzymology / Pancreatic Neoplasms - pathology / Phosphoinositide-3 Kinase Inhibitors / PNAS Plus / Protein Conformation / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Proto-Oncogene Proteins c-myc - antagonists & inhibitors / Proto-Oncogene Proteins c-myc - physiology / Pyrans - pharmacology / Pyrans - therapeutic use / Signal Transduction - drug effects / Thiophenes - pharmacology / Thiophenes - therapeutic use / Transcription Factors - antagonists & inhibitors / Transcription Factors - chemistry / Transcription Factors - physiology / Xenograft Model Antitumor Assays