4 research outputs found
Battling Btk Mutants With Noncovalent Inhibitors That Overcome Cys481 and Thr474 Mutations
The
Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib has
shown impressive clinical efficacy in a range of B-cell malignancies.
However, acquired resistance has emerged, and second generation therapies
are now being sought. Ibrutinib is a covalent, irreversible inhibitor
that modifies Cys481 in the ATP binding site of Btk and renders the
enzyme inactive, thereby blocking B-cell receptor signal transduction.
Not surprisingly, Cys481 is the most commonly mutated Btk residue
in cases of acquired resistance to ibrutinib. Mutations at other sites,
including Thr474, a gatekeeper residue, have also been detected. Herein,
we describe noncovalent Btk inhibitors that differ from covalent inhibitors
like ibrutinib in that they do not interact with Cys481, they potently
inhibit the ibrutinib-resistant Btk C481S mutant <i>in vitro</i> and in cells, and they are exquisitely selective for Btk. Noncovalent
inhibitors such as GNE-431 also show excellent potency against the
C481R, T474I, and T474M mutants. X-ray crystallographic analysis of
Btk provides insight into the unique mode of binding of these inhibitors
that explains their high selectivity for Btk and their retained activity
against mutant forms of Btk. This class of noncovalent Btk inhibitors
may provide a treatment option to patients, especially those who have
acquired resistance to ibrutinib by mutation of Cys481 or Thr474
Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349
Aberrant activation of the PI3K-Akt-mTOR signaling pathway
has
been observed in human tumors and tumor cell lines, indicating that
these protein kinases may be attractive therapeutic targets for treating
cancer. Optimization of advanced lead <b>1</b> culminated in
the discovery of clinical development candidate <b>8h</b>, GDC-0349,
a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349
demonstrates pathway modulation and dose-dependent efficacy in mouse
xenograft cancer models
Structure-Guided Rescaffolding of Selective Antagonists of BCL‑X<sub>L</sub>
Because
of the promise of BCL-2 antagonists in combating chronic
lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL),
interest in additional selective antagonists of antiapoptotic proteins
has grown. Beginning with a series of selective, potent BCL-X<sub>L</sub> antagonists containing an undesirable hydrazone functionality,
in silico design and X-ray crystallography were utilized to develop
alternative scaffolds that retained the selectivity and potency of
the starting compounds
Identification of <i>C</i>‑2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2
Herein we report on the structure-based
discovery of a <i>C</i>-2 hydroxyethyl moiety which provided
consistently high
levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine
series of JAK1 inhibitors. X-ray structures of a <i>C</i>-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed
differential ligand/protein interactions between the two isoforms
and offered an explanation for the observed selectivity. Analysis
of historical data from related molecules was used to develop a set
of physicochemical compound design parameters to impart desirable
properties such as acceptable membrane permeability, potent whole
blood activity, and a high degree of metabolic stability. This work
culminated in the identification of a highly JAK1 selective compound
(<b>31</b>) exhibiting favorable oral bioavailability across
a range of preclinical species and robust efficacy in a rat CIA model