Protein Tyrosine Phosphatase non-receptor type 11 (PTPN11; encoding protein SHP2) is an important protein tyrosine phosphatase (PTP) in the human body and plays an important role in regulating cell proliferation and differentiation. Overexpression of SHP2 will promote the development of cancer diseases, so research on SHP2 inhibitors has become one of the popular targets for the treatment of cancer. Recent studies have shown that combining SHP099 (an allosteric site 1 inhibitor) with SHP844 (an allosteric site 2 inhibitor) will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamics simulations to explore the inhibition mechanism of SHP099 and SHP844 on SHP2 protein. The result shows that the interactions of allosteric site 1 (THR108-TRP112, LEU236-GLN245), allosteric site 2 (GLN79-GLN87, LEU262-GLN269), P-loop (HIS458-ARG465), and Q-loop (ARG501-THR507) are obviously enhanced in SHP2-SHP099-SHP844 system, which makes the fluctuation of residues more stable and the active site more difficult to be exposed. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that led to the SHP2 protein in auto-inhibition conformation. This study provides an idea that help people to understand the mechanism of inhibition of the combining SHP099 with SHP844 on the SHP2.
Background: Deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A) is prevalent in pediatric acute lymphoblastic leukemia (ALL) and the prognostic importance of CDKN2A deletion is still controversial. Procedure: A total of newly diagnosed 655 pediatric ALL cases were treated with Chinese Children’s Leukemia Group-acute lymphoblastic leukemia 2015 (CCLG-ALL 2015) protocol. We investigated the difference among B-ALL and T-ALL patients with CDKN2A deletion for clinical characteristics at diagnosis, immunophenotype, risk stratification, cytogenetic risk group, and early treatment responses.We also analyzed the prognostic markers for event-free survival(EFS) in CDKN2A-deleted patients. Result: The incidence of CDKN2A gene deletion was presented in 14.6% (87/595) of B-ALL subgroup and 40.0% (24/60) of T-ALL subgroup. T-ALL subgroup was characterized by a higher male/female ratio, a higher proportion of older children (>10 years old) and WBC counts of greater than 50x109/L compared to B-ALL(P<0.05). In the univariate analysis, CNS 2, cytogenetic risk groups, prednisone poor responders (PPR), poor early response (PER), and MRD≥0.01% at day 46 (P<0.05) were associated with a poor event-free survival. Multivariable analysis revealed that PPR and MRD≥0.01% at day 46 were independent inferior prognostic factors for event-free survival(P<0.05). Conclusions: The incidence of CDKN2A deletion was more prevalent in T-ALL. CDKN2A deletion was significantly more prevalent in older (>10 years old) boys with leukocyte counts of greater than 50x109/L among T-ALL. PPR and MRD≥0.01% at day 46 were an independent prognostic factor for EFS in pediatric CDKN2A-deleted ALL.