Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph ؉ metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P ‫؍‬ .0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P ‫؍‬ .057 and P ‫؍‬ .034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. IntroductionChronic myeloid leukemia (CML) is a clonal hematologic malignancy that results from transformation of a multipotent hemopoietic stem cell. [1][2][3] The molecular hallmark of CML is the formation of a BCR-ABL fusion gene, usually formed as a consequence of the Philadelphia (Ph) translocation involving chromosomes 9 and 22. 4-6 BCR-ABL plays a pivotal role in the pathogenesis of CML and its formation is likely to represent the initiating event. In support of this concept transgenic and retroviral transduction studies have demonstrated that expression of BCR-ABL in murine bone marrow cells resulted in leukemia, with some cases closely resembling CML. [7][8][9][10][11][12][13] In one recent transgenic model the leukemia could be reversed by down-regulating BCR-ABL. 14 Chronic myeloid leukemia is a biphasic disease with an initial chronic phase that is readily controlled. However, this is followed by an ill-defined accelerated phase, and then a terminal blastic phase that resembles an acute leukemia, which is usually refractory to therapy. Transformation to blast crisis is accompanied by secondary cytogenetic changes in about 85% of cases, 15 but the molecular basis for this transformation is poorly understood. A number of molecular changes have been identified in a minority of cases of blast crisis, including mutations or deletions of p53, p16 INKA , and the retinoblastoma protein, and mutation or overexpression of Ras and EVI-1. 1,2 However, none provide a method for prospectively distinguishing those patients who will progress rapidly to blast...

The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress.Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.

Relative to other polycyclic frameworks (1−3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X 7 receptor (P2X 7 R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.

A wide range of primary, secondary and tertiary propargylic alcohols undergo a Meyer-Schuster rearrangement to give enones at room temperature in the presence of a gold(I) catalyst and small quantities of MeOH or 4-methoxyphenylboronic acid. The syntheses of the enone natural products isoegomaketone and daphenone were achieved using this reaction as the key step. The rearrangement of primary propargylic alcohols can readily be combined in a one-pot procedure with the addition of a nucleophile to the resulting terminal enone, to give β-aryl, β-alkoxy, β-amino or β-sulfido ketones. Propargylic alcohols bearing an adjacent electron-rich aryl group can also undergo silver-catalyzed substitution of the alcohol with oxygen, nitrogen and carbon nucleophiles. This latter reaction was initially observed with a batch of gold catalyst that was probably contaminated with small quantities of silver salt.

Meyer-Schuster rearrangements of propargylic alcohols take place readily at room temperature in toluene with 1-2 mol % PPh(3)AuNTf(2), in the presence of 0.2 equiv of 4-methoxyphenylboronic acid or 1 equiv of methanol. Good to excellent yields of enones can be obtained from secondary and tertiary alcohols, with high selectivity for the E-alkene in most cases. A one-pot procedure for the conversion of primary propargylic alcohols into β-arylketones was also developed, via Meyer-Schuster rearrangement followed by Pd-catalayzed addition of a boronic acid.