**14.3. DNA damage and cell cycle**

*p53 inhibitors:* Since p53 is frequently mutated in tumours, therapeutic approaches have been made to restore p53 function. Since p53 is targeted to degradation through interaction with mdm2, some drugs such as RITA, Nutlin-3 or HLI198 have been designed to disrupt p53 mdm2 interaction. These compounds bind to the p53 binding site on mdm2 or inhibit mdm2 ubiquitin ligase activity. This approach is valid in cancers with wild type p53, such as haematological malignancies [56]. A second approach is to rescue wild-type 53 function in p53-mutated tumours. PRIMA-1 restores sequence-specific DNA binding and active conformation of mutant p53 proteins. PRIMA-1 can synergize with conventional chemotherapeutic drugs and inhibit tumour growth in mice with no apparent toxicity and has recently entered clinical trials [78].

*Chk1/2 inhibitors:* The concept of "synthetic lethality" coined by Kaelin, by which two molecular lesions combine to have a lethal effect on the cell, although neither of them is harmful individually, has recently gained interest [193,194]. In this context, Chk inhibitors may have a therapeutic potential in p53-mutated tumours. UCN-01, the first Chk inhibitor evaluated in humans, has limited clinical value due to its toxicity. Other Chk inhibitors functioning as checkpoint abrogators that are being evaluated in clinical trials are: AZD7762, LY26303618, CBT501, PF-00477736, SCH 900776, XL844, and the wee-1 inhibitor MK-1775 [195,196].

*PARP inhibitors:* Other example of synthetic lethality is BRCA mutant breast cancer. BRCA1 and BRCA2 play a role in homologous recombination, an important repair pathway for DNA double strand breaks. The current hypothesis is that since PARP is involved in repairs in DNA single strands breaks, inhibition of PARP leads to accumulation of single strand unrepaired breaks and becomes synthetically lethal in BRCA-mutated cancers [197]. Several PARP inhibitors are being evaluated in clinical trials: AG014699, AZD2281 (olaparib), ABT888 (veliparib), BSI-201 (iniparib), INO-1001, GP121016, CEP-9722 and MKI4827 [197,198]. PARP inhibitors may be useful in tumours bearing other types of genomic or functional defects in DNA damage response pathways.
