3 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
Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study
Because
of their increased activity against activating mutants,
first-generation epidermal growth factor receptor (EGFR) kinase inhibitors
have had remarkable success in treating non-small-cell lung cancer
(NSCLC) patients, but acquired resistance, through a secondary mutation
of the gatekeeper residue, means that clinical responses only last
for 8–14 months. Addressing this unmet medical need requires
agents that can target both of the most common double mutants: T790M/L858R
(TMLR) and T790M/delÂ(746-750) (TMdel). Herein we describe how a noncovalent
double mutant selective lead compound was optimized using a strategy
focused on the structure-guided increase in potency without added
lipophilicity or reduction of three-dimensional character. Following
successive rounds of design and synthesis it was discovered that cis-fluoro
substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided
synergistic, substantial, and specific potency gain through direct
interaction with the enzyme and/or effects on the proximal ligand
oxygen atom. Further development of the fluorohydroxypiperidine series
resulted in the identification of a pair of diastereomers that showed
50-fold enzyme and cell based selectivity for T790M mutants over wild-type
EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft
model
Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors
A therapeutic rationale is proposed for the treatment
of inflammatory diseases, such as rheumatoid arthritis (RA), by specific
targeting of the JAK1 pathway. Examination of the preferred binding
conformation of clinically effective, pan-JAK inhibitor <b>1</b> led to identification of a novel, tricyclic hinge binding scaffold <b>3</b>. Exploration of SAR through a series of cycloamino and cycloalkylamino
analogues demonstrated this template to be highly tolerant of substitution,
with a predisposition to moderate selectivity for the JAK1 isoform
over JAK2. This study culminated in the identification of subnanomolar
JAK1 inhibitors such as <b>22</b> and <b>49</b>, having
excellent cell potency, good rat pharmacokinetic characteristics,
and excellent kinase selectivity. Determination of the binding modes
of the series in JAK1 and JAK2 by X-ray crystallography supported
the design of analogues to enhance affinity and selectivity