6 research outputs found
Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors
SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript
Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight
MELK
kinase has been implicated in playing an important role in
tumorigenesis. Our previous studies suggested that MELK is involved
in the regulation of cell cycle and its genetic depletion leads to
growth inhibition in a subset of high MELK-expressing basal-like breast
cancer cell lines. Herein we describe the discovery and optimization
of novel MELK inhibitors <b>8a</b> and <b>8b</b> that
recapitulate the cellular effects observed by short hairpin ribonucleic
acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered
a novel fluorine-induced hydrophobic collapse that locked the ligand
in its bioactive conformation and led to a 20-fold gain in potency.
These novel pharmacological inhibitors achieved high exposure in vivo
and were well tolerated, which may allow further in vivo evaluation
Optimization of 3‑Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1
High throughput screening and subsequent
hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one
as a potent inhibitor of IDH1<sup>R132H</sup>. Synthesis of the four
separate stereoisomers identified the (<i>S</i>,<i>S</i>)-diastereomer (<b>IDH125</b>, <b>1f</b>) as
the most potent isomer. This also showed reasonable cellular activity
and excellent selectivity vs IDH1<sup>wt</sup>. Initial structure–activity
relationship exploration identified the key tolerances and potential
for optimization. X-ray crystallography identified a functionally
relevant allosteric binding site amenable to inhibitors, which can
penetrate the blood–brain barrier, and aided rational optimization.
Potency improvement and modulation of the physicochemical properties
identified (<i>S</i>,<i>S</i>)-oxazolidinone <b>IDH889</b> (<b>5x</b>) with good exposure and 2-HG inhibitory
activity in a mutant IDH1 xenograft mouse model
Identification of NVP-TNKS656: The Use of Structure–Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor
Tankyrase
1 and 2 have been shown to be redundant, druggable nodes
in the Wnt pathway. As such, there has been intense interest in developing
agents suitable for modulating the Wnt pathway in vivo by targeting
this enzyme pair. By utilizing a combination of structure-based design
and LipE-based structure efficiency relationships, the core of XAV939
was optimized into a more stable, more efficient, but less potent
dihydropyran motif <b>7</b>. This core was combined with elements
of screening hits <b>2</b>, <b>19</b>, and <b>33</b> and resulted in highly potent, selective tankyrase inhibitors that
are novel three pocket binders. NVP-TNKS656 (<b>43</b>) was
identified as an orally active antagonist of Wnt pathway activity
in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic
signature of binding, highly favorable physicochemical properties,
and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor
that is well suited for further in vivo validation studies
Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers
SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases
Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors
Herein, we describe the discovery of potent and highly
selective
inhibitors of both CDK4 and CDK6 via structure-guided optimization
of a fragment-based screening hit. CDK6 X-ray crystallography and
pharmacokinetic data steered efforts in identifying compound <b>6</b>, which showed >1000-fold selectivity for CDK4 over
CDKs 1 and 2 in an enzymatic assay. Furthermore, <b>6</b> demonstrated
in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1
mouse xenograft model