Targeting the DNA Damage Response for Anti-Cancer Therapy by John Pollard & Nicola Curtin

Author:John Pollard & Nicola Curtin
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

The concept of utilising intramolecular hydrogen bonding interactions to constrain molecules in defined conformations is well known and has been used successfully in “scaffold hop” strategies where covalently bonded cyclic systems have been replaced with hydrogen bonded constrained acyclic systems (Furet et al. 2008). In the case of the quinoline carboxamide scaffold there already exists such a hydrogen bonded constrained acyclic system between the 4-amino substituent and the 3-carboxamide substituent suggesting that replacement with a covalently bonded cyclic system may be feasible. Such an approach would result in a significant reduction in hydrogen bond donors. The feasibility of this approach was confirmed by the synthesis of the imidazo[5,4-c]quinolin-2-one containing compound 16 (Fig. 8.5). Indeed, the dual PI3K/mTOR inhibitor NVP-BEZ235 (compound 4), described earlier, contains this same imidazo[5,4-c]quinolin-2-one scaffold, thus providing further evidence of the ability of this scaffold to inhibit ATM, whilst simultaneously highlighting the challenge of achieving the required level of selectivity, not apparent in the earlier example.

Comparison of quinoline carboxamide (17) with the analogous imidazo[5,4-c]quinolin-2-one (16), shows that ATM potency is broadly maintained (17: ATM cell IC50 = 0.95 μM, 16: ATM cell IC50 = 0.36 μM); however, the selectivity of compound 16 against closely related kinases was significantly reduced and indeed 16 was shown to have greater affinity for ATR than for ATM (16: ATR cell IC50 = 0.087 μM). Imidazo[5,4-c]quinolin-2-one,16, did show the anticipated increase in permeability and reduction in efflux compared to quinoline carboxamide analogue 17. This improved permeability was achieved with only a modest increase in lipophilicity (Δ log D 7.4 = 0.3), supporting the hypothesis that the imidazo[5,4-c]quinolin-2-one is an inherently more permeable scaffold and that this is predominantly driven by reduced number of hydrogen bond donors.

With the identification of a more permeable scaffold attention was once again turned to the incorporation of basic functionality to drive increased Vss and half-life. Significant optimisation of the basic substituent delivered not only improved properties and pharmacokinetics but also delivered a dramatic improvement in ATM affinity and selectivity, as exemplified by compound 18, subsequently known as AZD0156, Fig. 8.6.

Fig. 8.6Structure of screening AZD0156 (18)

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