2 research outputs found
Targeting cancer with small molecule pan-KRAS degraders
Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders
Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold
Inhibition
of indoleamine 2,3-dioxygenase (IDO1) is an attractive
immunotherapeutic approach for the treatment of a variety of cancers.
Dysregulation of this enzyme has also been implicated in other disorders
including Alzheimer’s disease and arthritis. Herein, we report
the structure-based design of two related series of molecules: <i>N</i>1-substituted 5-indoleimidazoles and <i>N</i>1-substituted 5-phenylimidazoles. The latter (and more potent) series
was accessed through an unexpected rearrangement of an imine intermediate
during a Van Leusen imidazole synthesis reaction. Evidence for the
binding modes for both inhibitor series is supported by computational
and structure–activity relationship studies