39 research outputs found
Stereoselective Synthesis of E,Z-Configured 1,3-Dienes by Ring-Closing Metathesis. Application to the Total Synthesis of Lactimidomycin
Strategic positioning of a silyl group on the diene unit of a diene-ene substrate allows rigorous regio- and stereocontrol to be exerted during metathesis-based macrocyclization reactions. The versatility of this concise approach to E,Z-configured 1,3-dienes of ring sizes of 12 or larger is demonstrated by an application to the total synthesis of lactimidomycin, a potent translation and cell-migration inhibitor
Selective small molecule induced degradation of the BET bromodomain protein BRD4
The Bromo- and Extra-Terminal (BET)
proteins BRD2, BRD3, and BRD4
play important roles in transcriptional regulation, epigenetics, and
cancer and are the targets of pan-BET selective bromodomain inhibitor
JQ1. However, the lack of intra-BET selectivity limits the scope of
current inhibitors as probes for target validation and could lead
to unwanted side effects or toxicity in a therapeutic setting. We
designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to
a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the
intracellular destruction of BET proteins. Compound MZ1 potently and
rapidly induces reversible, long-lasting, and unexpectedly selective
removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent
on binding to VHL but is achieved at a sufficiently low concentration
not to induce stabilization of HIF-1α. Gene expression profiles
of selected cancer-related genes responsive to JQ1 reveal distinct
and more limited transcriptional responses induced by MZ1, consistent
with selective suppression of BRD4. Our discovery opens up new opportunities
to elucidate the cellular phenotypes and therapeutic implications
associated with selective targeting of BRD4
Epigenetic polypharmacology: from combination therapy to multitargeted drugs
The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed