Antitumor Activity of RXDX-105 in Multiple Cancer Types with Rearrangements or Mutations.

While multikinase inhibitors with RET activity are active in -rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET.

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer.

Unlabelled: Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed.

Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.

A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q.

Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo.

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.

Small molecule activation of PKM2 in cancer cells induces serine auxotrophy.

Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode.

Structure-based library design in efficient discovery of novel inhibitors.

Structure-based library design employs both structure-based drug design (SBDD) and combinatorial library design. Combinatorial library design concepts have evolved over the past decade, and this chapter covers several novel aspects of structure-based library design together with successful case studies in the anti-viral drug design HCV target area. Discussions include reagent selections, diversity library designs, virtual screening, scoring/ranking, and post-docking pose filtering, in addition to the considerations of chemistry synthesis.

Thiazolone-acylsulfonamides as novel HCV NS5B polymerase allosteric inhibitors: convergence of structure-based drug design and X-ray crystallographic study.

A novel series of thiazolone-acylsulfonamides were designed as HCV NS5B polymerase allosteric inhibitors. The structure based drug designs (SBDD) were guided by docking results that revealed the potential to explore an additional pocket in the allosteric site. In particular, the designed molecules contain moieties of previously described thiazolone and a newly designed acylsulfonamide linker that is in turn connected with a substituted aromatic ring.

Structure-activity relationship (SAR) studies of quinoxalines as novel HCV NS5B RNA-dependent RNA polymerase inhibitors.

From chemical compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a substituted quinoxaline hit with an IC(50) of 5.5 microM. A series of substituted quinoxaline amide derivatives were synthesized based on the hit's pharmacophore, and a good structure-activity relationship was observed.

Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase.

A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC(50)=50 nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R(1) phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.

Isothiazoles as active-site inhibitors of HCV NS5B polymerase.

Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polymerase. The best compound has an IC(50) of 200 nM and EC(50) of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of 1 with HCV NS5B was obtained at a resolution of 2.

Novel thiazolones as HCV NS5B polymerase allosteric inhibitors: Further designs, SAR, and X-ray complex structure.

Structure-activity relationships (SAR) of 1 against HCV NS5B polymerase were described. SAR explorations and further structure-based design led to the identifications of 2 and 3 as novel HCV NS5B inhibitors. X-ray structure of 3 in complex with NS5B polymerase was obtained at a resolution of 2.

Identification of novel, selective and potent Chk2 inhibitors.

A series of isothiazole carboxamidine compounds were synthesized and discovered as novel and selective inhibitors for Chk2. They are not active against the related Chk1 kinase. The structure-activity relationship studies were performed on the scaffold, and enzymatic kinetic analysis showed they are simple ATP competitive inhibitors with K(i) values as low as 11 nM for Chk2.

Identification of isothiazole-4-carboxamidines derivatives as a novel class of allosteric MEK1 inhibitors.

The development of potent, orally bioavailable, and selective series of 5-amino-3-hydroxy-N(1-hydroxypropane-2-yl)isothiazole-4-carboxamidine inhibitors of MEK1 and MEK-2 kinase is described. Optimization of the carboxamidine and the phenoxyaniline group led to the identification of 55 which gave good potency as in vitro MEK1 inhibitors, and good oral exposure in rat.

Structure-based design of a novel thiazolone scaffold as HCV NS5B polymerase allosteric inhibitors.

A structure-based approach was performed to design a novel thiazolone scaffold as HCV NS5B inhibitors. A focused library was designed and docked by GOLD. One of the top-scored molecules was synthesized and shown to have similar potency to the initial hit.

Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents.

Background: The cyclooxygenase-2 (COX-2) inhibitor celecoxib is thought to act as a chemopreventive agent by sensitizing cancer cells to apoptotic signals. Other COX-2 inhibitors, such as rofecoxib, are two orders of magnitude less potent than celecoxib at inducing apoptosis. The molecular structures of celecoxib and rofecoxib were used as starting points to examine the structural features that contribute to this discrepancy.