Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors

[Image: see text] Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure–activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL

Among the various subtypes of Acute Myeloid Leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies due to an attenuated response by p53, which induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR and ATM inhibition represent potential alternative therapeutic strategies for the treatment of AML, especially MLL-driven leukemias

Discovery of Novel 3‑Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (<b>4</b>), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1<i>R</i>)-1-(tetrahydro-2<i>H</i>-pyran-4-yl)­ethyl]­amino}-3-quinolinecarboxamide (<b>72</b>) and 7-fluoro-6-[6-(methoxymethyl)­pyridin-3-yl]-4-{[(1<i>S</i>)-1-(1-methyl-1<i>H</i>-pyrazol-3-yl)­ethyl]­amino}­quinoline-3-carboxamide (<b>74</b>) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. <b>72</b> and <b>74</b> constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model