5 research outputs found
Preclinical characterization of ABT-348, a kinase inhibitor targeting the Aurora, VEGFR/PDGFR, and SRC kinase families
Discovery and Evaluation of a Series of 3-Acylindole Imidazopyridine Platelet-Activating Factor Antagonists 1
Discovery of <i>N</i>‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1<i>H</i>‑pyrrolo[2,3‑<i>c</i>]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor
The development of bromodomain and
extraterminal domain (BET) bromodomain inhibitors and their examination
in clinical studies, particularly in oncology settings, has garnered
substantial recent interest. An effort to generate novel BET bromodomain
inhibitors with excellent potency and drug metabolism and pharmacokinetics
(DMPK) properties was initiated based upon elaboration of a simple
pyridone core. Efforts to develop a bidentate interaction with a critical
asparagine residue resulted in the incorporation of a pyrrolopyridone
core, which improved potency by 9–19-fold. Additional structure–activity
relationship (SAR) efforts aimed both at increasing potency and improving
pharmacokinetic properties led to the discovery of the clinical candidate <b>63</b> (ABBV-075/mivebresib), which demonstrates excellent potency
in biochemical and cellular assays, advantageous exposures and half-life
both in animal models and in humans, and in vivo efficacy in mouse
models of cancer progression and inflammation
Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors
Members
of the BET family of bromodomain containing proteins have been identified
as potential targets for blocking proliferation in a variety of cancer
cell lines. A two-dimensional NMR fragment screen for binders to the
bromodomains of BRD4 identified a phenylÂpyridazinone fragment
with a weak binding affinity (<b>1</b>, <i>K</i><sub>i</sub> = 160 μM). SAR investigation of fragment <b>1</b>, aided by X-ray structure-based design, enabled the synthesis of
potent pyridone and macrocyclic pyridone inhibitors exhibiting single
digit nanomolar potency in both biochemical and cell based assays.
Advanced analogs in these series exhibited high oral exposures in
rodent PK studies and demonstrated significant tumor growth inhibition
efficacy in mouse flank xenograft models
Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors
Members
of the BET family of bromodomain containing proteins have been identified
as potential targets for blocking proliferation in a variety of cancer
cell lines. A two-dimensional NMR fragment screen for binders to the
bromodomains of BRD4 identified a phenylÂpyridazinone fragment
with a weak binding affinity (<b>1</b>, <i>K</i><sub>i</sub> = 160 μM). SAR investigation of fragment <b>1</b>, aided by X-ray structure-based design, enabled the synthesis of
potent pyridone and macrocyclic pyridone inhibitors exhibiting single
digit nanomolar potency in both biochemical and cell based assays.
Advanced analogs in these series exhibited high oral exposures in
rodent PK studies and demonstrated significant tumor growth inhibition
efficacy in mouse flank xenograft models