The DNA damage response is an important barrier to tumorigenesis. Impairment of p53 function is crucial to tumorigenesis by allowing evasion of p53 dependent responses. The mechanisms involve either (i) missense mutations, (ii) partial abrogation of signaling pathways or effector molecules that regulate p53, (iii) epigenetic deregulation. The tyrosine to cysteine mutation, Y220C, in p53 is found in around 100,000 new cancer cases per annum. This mutation destabilizes the core domain by 4 kcal mol-1 and destabilizes p53 under physiological conditions. The large to small mutation results in the fusing of two shallow pockets to create an extended surface cleft that a number of different fragments bind. The small molecule PK083, 1-(-ethyl-9H-carbazol-3-yl)-N-methanamine, binds the mutant-specific crevice with a KD = 150 μM and raised the protein mutant's half-life to over 15 minutes vs. 4 minutes in the absence of the ligand. This presents an ideal starting point towards the design of a p53 rescuing drug. A library of carbazoles was designed and synthesized, guided by SAR studies, crystallographic information and computational chemistry, with the aim of optimizing the structure toward a more potent PK083 analogue. Affinity gains were achieved by exploitation of direct fluorine-protein interactions between PK9255 (N-methyl-1-(9- (2,2,2-trifluoroethyl)-9H-carbazol-3-yl)methanamine), and the backbone carbonyls of Leu145 and Trp146 and the thiol of Cys220, resulting in a Kd = 28 μM. Further affinity gains were achieved through SAR studies targeting the proline-rich subsite II. Chemistry was optimized to allow a diversity-oriented synthesis toward 2,6,9- substituted carbazoles. A small library of PK083 analogues, where the subsite II targeting group was a halogen, ether, ester, amide or heterocycle were synthesized, identifying the heterocyclic compounds as most potent. A scan of heterocyclic compounds was carried out to identify the most potent heterocyclic substitution.