Design and Synthesis of Thiadiazoles and Thiazoles Targeting the Bcr‐Abl T315I Mutant: from Docking False Positives to ATP‐Noncompetitive Inhibitors

Chronic myeloid leukemia (CML) was the first neoplastic disease for which the knowledge of the molecular pathogenesis led to the development of a curative therapy. Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland), the first targeted drug for the treatment of CML, has a high rate of remission and is currently used as frontline therapy. However, patients treated with imatinib (IM) can develop resistance to the drug leading to leukemia progression. Multiple mechanisms of resistance have been identified, though the dominant mechanism seems to be represented by amino acid point mutations within the kinase domain of Bcr-Abl. Second generation Bcr-Abl inhibitors (such as dasatinib and nilotinib) are capable of inhibiting many IM-resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the highly conserved gatekeeper residue Thr 315 (T315I). This specific mutation accounts for 15 % of all point mutations and confers complete resistance to all ATP-competitive Bcr-Abl inhibitors currently on the market. The mutation of the gatekeeper residue in Bcr-Abl (Thr 315) to a bulkier hydrophobic residue (such as isoleucine) often causes the loss of an important hydrogen bond necessary for high-affinity inhibitor binding and creates steric hindrance that could interfere with inhibitor binding within the ATP-binding pocket. In addition, recent studies showed that bulkier hydrophobic residues in position 315 tend to stabilize a “hydrophobic spine”, shifting the equilibrium towards the active conformation of Bcr-Abl. For this reason, targeting Bcr-Abl with compounds able to avoid unfavorable clashes with Ile 315 is becoming an effective strategy in the search for new drugs active on the highly resistant T315I mutant. The aurora kinase/Abl inhibitors VX-680 (1), PHA-739358 (2) and the Abl inhibitor PPY-A (3) are rare examples of ATP-competitive inhibitors that are also able to inhibit those enzymes with the T315I mutation.