Mcl-1 is a member of the Bcl-2 family of proteins. It is frequently amplified or overexpressed and represents a common resistance mechanism which is one of the “top ten” most commonly amplified genomic regions in human cancer. Multiple myeloma, non-small cell lung, and breast cancers with high Mcl-1 protein levels show resistance to standard therapies and poor prognosis for patients. Mcl-1 loss leads to rapid apoptosis and tumor regression in multiple human cancers. Using structure based drug design, we designed a macrocyclic inhibitor, AZD5991 with an axial chiral center. AZD5991 has excellent Mcl-1 binding and cellular activity and induces rapid tumor regression in multiple mouse xenograft models. AZD5991 will be evaluated in a Phase I study to evaluate its safety, pharmacokinetics and initial activity in patients with hematological cancers. The first synthesis of AZD5991 was a 27-step sequence with a longest linear sequence of 15 steps and 3% overall yield. The axial chiral center was introduced via a Suzuki coupling and the enantiomers were resolved by chiral SFC at the end of the synthesis, leading to low recovery rate, partially due to poor solubility of the racemate. A Mitsunobu reaction was used to perform the macrocyclization. We initially optimized the route in order to provide a large quantity of material for biological testing. The second-generation route shortened the original linear sequence by 5 steps and increased the recovery rate of the chiral separation, resulting an improved 15% overall yield. On larger scale, Mitsunobu macrocyclization proved to be sensitive to the quality of the starting material with yields varying widely. In subsequent synthetic optimizations of the route to AZD5991 and other related analogs, we developed a simple SN2 alkylation macrocyclization to overcome these issues with 85% yield. The overall route was made more convergent, and synthesis of building blocks was also shortened. Many of these optimizations were incorporated into the GMP synthesis of material for GLP toxicology studies and Phase I clinical trials.

Total synthesis and route optimization of Mcl-1 antagonist clinical candidate drug AZD5991

254th National Meeting (2017)

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