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Experimental Therapeutics, Preclinical Pharmacology |
Northern Institute for Cancer Research, The University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom [C. R. C., M. A. B., H. D. T., B. W. D., L-Z. W., S. K., A. H. C., D. R. N., N. J. C.], and Pfizer Global Research and Development/Agouron Pharmaceuticals, Inc., La Jolla, California [D. S., J. L., C. Z., T. B., K. M., Z. H.]
The nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) facilitates DNA repair, and is, therefore, an attractive target for anticancer chemo- and radio-potentiation. Novel benzimidazole-4-carboxamides (BZ1–6) and tricyclic lactam indoles (TI1–5) with PARP-1 Ki values of <10 nM have been identified.
Whole cell PARP-1 inhibition, intrinsic cell growth inhibition, and chemopotentiation of the cytotoxic agents temozolomide (TM) and topotecan (TP) were evaluated in LoVo human colon carcinoma cells. The acute toxicity of the inhibitors was investigated in PARP-1 null and wild-type mice. Tissue distribution and in vivo chemopotentiation activity was determined in nude mice bearing LoVo xenografts.
At a nontoxic concentration (0.4 µM) the PARP-1 inhibitors potentiated TM-induced growth inhibition 1.0–5.3-fold and TP-induced inhibition from 1.0–2.1-fold. Concentrations of the PARP-1 inhibitors that alone inhibited cell growth by 50% ranged from 8 to 94 µM. Maximum potentiation of TM activity was achieved at nongrowth inhibitory concentrations (
1 µM) of potent PARP-1 inhibitors BZ5 and TI4. Whole cell PARP-1 inhibition by BZ3, BZ5, BZ6, TI1, and TI4 was confirmed by attenuation of DNA damage-induced NAD+ depletion. Selected inhibitors (TI1, TI3, and TI4), in contrast to the benchmark compound PD128763, caused only mild hypothermia in both PARP-1 null and wild-type mice. Excellent distribution of BZ5, TI1, and TI3 into tumor tissue was observed, and TI3 enhanced TM antitumor activity in vivo.
These studies have identified potent nontoxic PARP-1 inhibitors with structural modifications that promote aqueous solubility, tolerability, and tissue distribution. These compounds are important leads in the development of clinically viable PARP-1 inhibitors.
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