Clinical features of complex karyotype in newly diagnosed acute myeloid leukemia

Complex karyotype acute myeloid leukemia (CK-AML) has been classified as an adverse-risk subtype. Although a few reports have further classified CK-AML as typical (including monosomy of chromosomes 5, 7 and 17 or deletion of 5q, 7q and/or 17p) or atypical, the clinical features of these subtypes in Japanese patients remain unclear. We retrospectively analyzed a total of 115 patients with CK-AML, including 77 with typical CK-AML and 38 with atypical CK-AML. Median overall survival (OS) was significantly shorter in patients with typical CK-AML than atypical CK-AML (143 days vs. 369 days, P = 0.009). Among patients with typical CK-AML, those with monosomy 17 or deletion of 17p had significantly shorter OS than patients without such abnormalities (105 days vs. 165 days, P = 0.033). TP53 mutations were more predominant in patients with typical CK-AML than in patients with atypical CK-AML (69.7% vs. 32.4%, P < 0.001). Patients with typical CK-AML had a poor prognosis regardless of TP53 mutation status. Among patients with atypical CK-AML, however, prognosis was worse for those with the TP53 mutation than those without the mutation. In conclusion, prognosis is extremely poor for both typical CK-AML and atypical CK-AML with TP53 mutation

Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia : a Hokkaido Leukemia Net study

Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.3%) NPM1 mutations, and 30 (10.2%) CEBPA biallelic mutations. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. The results suggest that analyzing these gene mutations at diagnosis can inform selection of the optimal intensity of therapy for patients with CN-AML

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1‑(Imidazo[1,2‑<i>a</i>]pyridin-6-yl)pyridin-2(1<i>H</i>)‑one Derivatives

Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of p<i>K</i>_a < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo­[1,2-<i>a</i>]­pyridine ring (represented in compounds <b>6a</b> and <b>6b</b>), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)­oxy]-1-(2-cyclopropyl-3-methylimidazo­[1,2-<i>a</i>]­pyridin-6-yl)­pyridin-2­(1<i>H</i>)-one <b>10a</b>. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure–Activity Relationships of Novel 1‑(Imidazo[1,2‑<i>a</i>]pyridin-6-yl)pyridin-2(1<i>H</i>)‑one Derivatives

Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of p<i>K</i>_a < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo­[1,2-<i>a</i>]­pyridine ring (represented in compounds <b>6a</b> and <b>6b</b>), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)­oxy]-1-(2-cyclopropyl-3-methylimidazo­[1,2-<i>a</i>]­pyridin-6-yl)­pyridin-2­(1<i>H</i>)-one <b>10a</b>. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats