Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia.

The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity.

[Clinicopathological features of 67 cases of endometriosis-associated epithelial ovarian carcinoma.].

OBJECTIVE: To investigate clinicopathological features of endometriosis-associated epithelial ovarian carcinoma. METHODS: Retrospective follow-up study, clinicopathological data from patients with ovarian epithelial carcinoma were retrieved, analyzed and compared. Among the 727 cases, 34 were found to originate from endometriosis (group A), 33 were found to have co-existing ovarian endometriosis (group B), and the remaining 660 had no ovarian endometriosis at all (group C). RESULT: Seven hundred and twenty-seven epithelial ovarian carcinoma patients were identified and their clinicopathological data retrieved. Sixty-seven (9.2%) of these cases were found to have coexisting endometriosis. The frequency of malignant tumors arising from ovarian endometriosis in this case series was estimated to be 0.87% (34/3890). The mean (standard deviation) age in groups A, B, and C were (47.2 +/- 1.3), (47.8 +/- 1.2), (51.2 +/- 0.4) years, respectively, with patients in group C being significantly older (P = 0.013). Patients with coexisting ovarian endometriosis were mostly diagnosed at stage I (P = 0.000) and having subtype of clear-cell (P = 0.000), while other patients were mostly diagnosed at stage III (P = 0.001), and having subtype of serous carcinoma (P = 0.000). The estrogen receptor (ER) positivity was significantly lower in groups A and B than that in group C (22.2%, 31.6% vs 43.9%; P = 0.018), but the difference in positivity of progestogen receptor among the three groups did not reach statistical significance (22.2%, 15.8% vs 35.5%; P = 0.082). While the five-year overall survival rate for all patients was 55.6%, significant difference in overall survival among the three groups was found 78.9%, 92.8%, 51.9%, respectively, for groups A, B and C (P = 0.000). CONCLUSION: Patients of endometriosis-associated epithelial ovarian carcinoma, especially patients with tumors arising from endometriosis, were found to be younger, having a significant lower stage and a better survival, and were mostly diagnosed with the subtype of clear-cell.