Drugs in Clinical Pipeline: KU-55933

KU-55933 [2-morpholino-6-(thianthren-1-yl)-4H-pyran-4-one] is a novel, specific and very potent small molecule inhibitor of Ataxia-Telangiectasia Mutated (ATM) kinase. The serine/threonine protein kinase ATM signals to cell cycle and DNA repair components by phosphorylating downstream targets such as p53, CHK2, NBS1, and BRCA1. Mutation of ATM occurs in the human autosomal recessive disorder ataxia-telangiectasia, which is characterized by hypersensitivity to ionizing radiation and a failure of cells to arrest the cell cycle after the induction of DNA double-strand breaks. It has thus been proposed that ATM inhibition would cause cellular radio- and chemosensitization [1].

The activity of KU-55933 is as follows:

IC₅₀ (ATM enzyme assay) = 12.9 ± 0.1 nM

K_i (ATP) = 2.2 ± 0.3 nM

Common Name: KU-55933

Synonyms:  KU 55933; KU-55933; KU55933

IUPAC Name: 2-morpholino-6-(thianthren-1-yl)-4H-pyran-4-one

CAS Number: 587871-26-9

Mechanism of Action: Kinase Inhibitor; ATM Inhibitor

Indication: Various Cancers

Development Stage: Investigational

Company: KuDOS Pharmaceuticals

The cellular response to DNA damage is one of coordinated repair and moderation of proliferation. ATM is a protein kinase member of the phosphatidylinositol 3'-kinase (PI3K)–related kinase (PIKK) family that plays a critical role in the maintenance of genome integrity . The Mr 345 000 phospho-protein plays key roles in coordinating cellular responses to IR-induced DNA double-strand breaks. Mutation of ATM occurs in the human autosomal recessive disorder ataxia-telangiectasia (A-T), which is characterized by several symptoms, including cerebellar degeneration, oculocutaneous telangiectasia, growth retardation, immune deficiencies, and characteristics of premature aging. At the cellular level, A-T is characterized by a hypersensitivity to ionizing radiation and radiomimetic drugs, radioresistant DNA synthesis, and chromosomal instability. In addition, there is a failure of A-T cells to arrest the cell cycle after DNA damage, thus reducing the opportunity for the repair of the genome before DNA replication or mitosis. Exposure of normal cells to ionizing radiation results in cell cycle arrest and ATM appears to be critical for the induction of these events, orchestrating the response by the downstream signaling to other response factors [1].

KU-55933 exhibits an ATP competitive mechanism of action. Importantly, this potency is essentially restricted to ATM as it is at least 100-fold more potent against ATM than against the other PIKK family members tested and shows no activity against a panel of 60 unrelated kinases. Of key importance here was that the closest family member with regards to homology across the ATP-binding domain, ATR, was not inhibited at doses up to 100 µmol/L. Moreover, a classic hallmark of cells derived from A-T patients is their extreme sensitivity to ionizing radiation. KU-55933 can recapitulate this phenotype in a range of cell lines and that it does not additionally sensitize A-T cells to the effects of ionizing radiation [1].

KU-55933 shows specificity with respect to inhibition of other phosphatidylinositol 3'-kinase-like kinases. Cellular inhibition of ATM by KU-55933 was demonstrated by the ablation of ionizing radiation-dependent phosphorylation of a range of ATM targets, including p53, yH2AX, NBS1, and SMC1. KU-55933 did not show inhibition of UV light DNA damage induced cellular phosphorylation events. Exposure of cells to KU-55933 resulted in a significant sensitization to the cytotoxic effects of ionizing radiation and to the DNA double-strand break-inducing chemotherapeutic agents, etoposide, doxorubicin, and camptothecin. Inhibition of ATM by KU-55933 also caused a loss of ionizing radiation-induced cell cycle arrest. By contrast, KU-55933 did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage.

ATM, a protein deficient in patients with ataxia-telangiectasia disease, is traditionally considered as a nuclear protein kinase that functions as a signal transducer in response to DNA damage. It has recently been shown that ATM is also a cytoplasmic protein that mediates the full activation of Akt in response to insulin. Aberrant activation of Akt plays a pivotal role in cancer development. KU-55933, blocks the phosphorylation of Akt induced by insulin and insulin-like growth factor I in cancer cells that exhibit abnormal Akt activity. Moreover, KU-55933 inhibits cancer cell proliferation by inducing G1 cell cycle arrest. It does so through the downregulation of the synthesis of cyclin D1, a protein known to be elevated in a variety of tumors. In addition, KU-55933 treatment during serum starvation triggers apoptosis in these cancer cells. Results suggest that KU-55933 may be a novel chemotherapeutic agent targeting cancer resistant to traditional chemotherapy or immunotherapy due to aberrant activation of Akt. Furthermore, KU-55933 completely abrogates rapamycin-induced feedback activation of Akt. Combination of KU-55933 and rapamycin not only induces apoptosis, which is not seen in cancer cells treated only with rapamycin, but also shows better efficacy in inhibiting cancer cell proliferation than each drug alone. Therefore, combining KU-55933 with rapamycin may provide a highly effective approach for improving mammalian target of rapamycin–targeted anticancer therapy that is currently hindered by rapamycin-induced feedback activation of Akt [3].

References:

1. Hickson, I.; et. al. Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM. Cancer Res 2004, 64(24), 9152-9159.

2. Cockcroft, X.-L. F.; et. al. Pyranones useful as atm inhibitors. WO2003070726A1

3. Li, Y.; et. al. The ATM inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther 2010, 9(1), 113-125.