Small Molecule SHP2 Inhibitor LXQ-217 Affects Lung Cancer Cell Proliferation in Vitro and in Vivo.

BACKGROUND: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors. METHODS: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217. RESULTS: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs. CONCLUSIONS: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.

Design of Selective PARP-1 Inhibitors and Antitumor Studies.

Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.

Can minimally invasive puncture and drainage for hypertensive spontaneous Basal Ganglia intracerebral hemorrhage improve patient outcome: a prospective non-randomized comparative study.

BACKGROUND: The treatment of hypertensive spontaneous intracranial hemorrhage (ICH) is still controversial. The purpose of the present study was to investigate whether minimally invasive puncture and drainage (MIPD) could improve patient outcome compared with decompressive craniectomy (DC). METHODS: Consecutive patients with ICH (≧30 mL in basal ganglia within 24 hours of ictus) were non-randomly assigned to receive MIPD (group A) or DC (group B) hematoma evacuation. The primary outcome was death at 30 days after onset. Functional independence was assessed at 1 year using the Glasgow Outcome Scale. RESULTS: A total of 198 patients met the per protocol analysis (84 in group A and 114 in group B). The initial Glasgow Coma Scale (GCS) score was 8.1 ± 3.4 and the National Institutes of Health Stroke Scale (NIHSS) score was 20.8 ± 5.3. The mean hematoma volume (HV) was 56.7 ± 23.0 mL, and there was extended intraventricular hemorrhage (IVH) in 134 patients. There were no significant intergroup differences in the above baseline data, except group A had a higher mean age than that of group B (59.4 ± 14.5 vs. 55.3 ± 11.1 years, P = 0.025). The cumulative mortalities at 30 days and 1 year were 32.3% and 43.4%, respectively, and there were no significant differences between groups A and B. However, the mortality for patients ≦60 years, NIHSS < 15 or HV≦60 mL was significantly lower in group A than that in group B (all P < 0.05). The cumulative functional independence at 1 year was 26.8%, and the difference between group A (33/84, 39.3%) and group B (20/114, 17.5%) was significant (P = 0.001). Multivariate logistic regression analysis showed that a favorable outcome after 1 year was associated with the difference in therapies, age, GCS, HV, IVH and pulmonary infection (all P <0.05). CONCLUSIONS: For patients with hypertensive spontaneous ICH (HV≧30 mL in basal ganglia), MIPD may be a more effective treatment than DC, as assessed by a higher rate of functional independence at 1 year after onset as well as reduced mortality in patients ≦60 years of age, NIHSS < 15 or HV≦60 mL.