Brad Sleebs - Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra large with potent proapoptotic cell-based activity

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  Publication Details (including relevant citation   information):

  Journal   of Medicinal Chemistry (2011)   54(6),   1914-1926.


  ABT-737 and ABT-263 are potent inhibitors of the BH3   antiapoptotic proteins, Bcl-xL and Bcl-2. This class   of putative anticancer agents invariantly contains an   acylsulfonamide core. We have designed and synthesized a series   of novel quinazoline-based inhibitors of Bcl-2 and   Bcl-xL that contain a heterocyclic alternative to the   acylsulfonamide. These compounds exhibit submicromolar,   mechanism-based activity in human small-cell lung carcinoma cell   lines in the presence of 10% human serum. This comprises the   first successful demonstration of a quinazoline sulfonamide core   serving as an effective benzoylsulfonamide bioisostere.   Additionally, these novel quinazolines comprise only the second   known class of Bcl-2 family protein inhibitors to induce   mechanism-based cell death.

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