ACS Medicinal Chemistry Letters p. 2244 - 2252 (2020)
Update date:2022-08-05
Topics:
Miles, Dillon H.
Yan, Xuelei
Thomas-Tran, Rhiannon
Fournier, Jeremy
Sharif, Ehesan U.
Drew, Samuel L.
Mata, Guillaume
Lawson, Kenneth V.
Ginn, Elaine
Wong, Kent
Soni, Divyank
Dhanota, Puja
Shaqfeh, Stefan G.
Meleza, Cesar
Chen, Ada
Pham, Amber T.
Park, Timothy
Swinarski, Debbie
Banuelos, Jesus
Schindler, Ulrike
Walters, Matthew J.
Walker, Nigel P.
Zhao, Xiaoning
Young, Stephen W.
Chen, Jie
Jin, Lixia
Leleti, Manmohan Reddy
Powers, Jay P.
Jeffrey, Jenna L.
The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ(PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγoffers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγinhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγinhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγinhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.
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