Design and synthesis of selective FLT3 inhibitors via exploration of back pocket II.

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

Medicinal Chemistry Strategies for the Development of Bruton's Tyrosine Kinase Inhibitors against Resistance.

Despite significant efficacy, one of the major limitations of small-molecule Bruton's tyrosine kinase (BTK) agents is the presence of clinically acquired resistance, which remains a major clinical challenge. This Perspective focuses on medicinal chemistry strategies for the development of BTK small-molecule inhibitors against resistance, including the structure-based design of BTK inhibitors targeting point mutations, e.g., (i) developing noncovalent inhibitors from covalent inhibitors, (ii) avoiding steric hindrance from mutated residues, (iii) making interactions with the mutated residue, (iv) modifying the solvent-accessible region, and (v) developing new scaffolds. Additionally, a comparative analysis of multi-inhibitions of BTK is presented based on cross-comparisons between 2916 unique BTK ligands and 283 other kinases that cover 7108 dual/multiple inhibitions. Finally, targeting the BTK allosteric site and uding proteolysis-targeting chimera (PROTAC) as two potential strategies are addressed briefly, while also illustrating the possibilities and challenges to find novel ligands of BTK.

[Application of transorally inserted anvil (OrVil(TM)) in laparoscopic-assisted radical resection for Siewert type II adenocarcinoma of the esophagogastric junction].

OBJECTIVE: To study the safety and feasibility of transorally inserted anvil (OrVil(TM)) in laparoscopic-assisted radical resection for Siewert type II adenocarcinoma of the esophagogastric junction (AEG). METHODS: Clinical data (operative time, rate of thoracotomy, residual cancer in the proximal margin, and postoperative recovery) of 72 patients suffered from Siewert type II AEG were analyzed retrospectively, including 46 cases of applying OrVil(TM) in digestive tract reconstruction for laparoscopic-assisted radical resection and 26 cases of applying pouch clamp embedding anvil, between May 2009 and August 2012 in Department of Minimally Invasive Gastrointestinal Surgery at the Peking University Cancer Hospital and Institute. RESULTS: The length between proximal margin and superior border of tumor was (2.5±1.5) cm in OrVil(TM) group, significantly longer than that in the traditional group [(1.6±1.1) cm, P<0.01]. Moreover, the intraoperative frozen pathological positive incidence of cancer remnant was 2.2% (1/46), and rate of thoracotomy was 0, both of which were significantly lower as compared to the traditional group [23.1% (6/26) and 15.4% (4/26) respectively, both P<0.01]. However, intraoperative blood loss and postoperative complications did not differ between the two groups (both P>0.05). CONCLUSIONS: As for laparoscopic-assisted Siewert type II AEG radical resection, application of OrVil(TM) in digestive tract reconstruction is a safe surgical procedure, and can effectively reduce the rate of intra-operative thoracotomy, which is beneficial to postoperative recovery.

D2 dissection in laparoscopic and open gastrectomy for gastric cancer.

AIM: To evaluate the radicalness and safety of laparoscopic D2 dissection for gastric cancer. METHODS: Clinicopathological data from 209 patients with gastric cancer, who underwent radical gastrectomy with D2 dissection between January 2007 and February 2011, were analyzed retrospectively. Among these patients, 131 patients underwent laparoscopy-assisted gastrectomy (LAG) and 78 underwent open gastrectomy (OG). The parameters analyzed included operative time, blood loss, blood transfusion, morbidity, mortality, the number of harvested lymph nodes (HLNs), and pathological stage. RESULTS: There were no significant differences in sex, age, types of radical resection [radical proximal gastrectomy (PG + D2), radical distal gastrectomy (DG + D2) and radical total gastrectomy (TG + D2)], and stages between the LAG and OG groups (P > 0.05). Among the two groups, 127 cases (96.9%) and 76 cases (97.4%) had 15 or more HLNs, respectively. The average number of HLNs was 26.1 ± 11.4 in the LAG group and 24.2 ± 9.3 in the OG group (P = 0.233). In the same type of radical resection, there were no significant differences in the number of HLNs between the two groups (PG + D2: 21.7 ± 7.5 vs. 22.4 ± 9.3; DG + D2: 25.7 ± 11.0 vs. 22.3 ± 7.9; TG + D2: 30.9 ± 13.4 vs. 29.3 ± 10.4; P > 0.05 for all comparisons). Tumor free margins were obtained in all cases. Compared with OG group, the LAG group had significantly less blood loss, but a longer operation time (P < 0.001). The morbidity of the LAG group was 9.9%, which was not significantly different from the OG group (7.7%) (P = 0.587). The mortality was zero in both groups. CONCLUSION: Laparoscopic D2 dissection is equivalent to OG in the number of HLNs, regardless of tumor location. Thus, this procedure can achieve the same radicalness as OG.

[Observational study of formaldehyde in air, rain and fog water at a site on the Mangdang Mountain of Fujian, China].

Through 2,4-dinitrophenylhydrazine (DNPH) high-performance liquid chromatography (HPLC) method, the levels of formaldehyde in ambient air, rain and fog samples were measured in Mangdang Mountain, Fujian Province, from March to April 2009. The average concentrations of formaldehyde in ambient air, rain and fog are 4.0 x 10(-10), 2.19 micromol/L and 2.94 micromol/L, respectively. Based on previous researches, this study described formaldehyde hydrolysis and reacting with S(IV) and other chemical reaction processes in liquid phase, explaining the phenomenon that the solubility of formaldehyde in the liquid phase is higher than the theoretical value. On-site measured Henry coefficients (Hme) and the effective Henry coefficients (H*) were derived from concentration of formaldehyde in ambient air, rain and fog samples and references. Comparing Hme and H*, this study found that the measured liquid phase concentrations of formaldehyde are higher than the theoretical concentrations, consistent with the references. The further founding is that Hme/H* in fog is higher than in rain, proving the result of Mangdang Mountain that the concentration of formaldehyde in fog is higher than in rain. Considering the climatic characteristics of Mangdang Mountain in spring, the wet deposition of formaldehyde is an important way in this area.