3 research outputs found
Regioselective Formal Hydroamination of Styrenes with 1‑Phenyl‑1<i>H</i>‑tetrazole-5-thiol
1-Phenyl-1<i>H</i>-tetrazole-5-thiol <b>1</b> (PT-thiol)
is employed in a unique Markovnikov-selective formal hydroamination
of styrenyl compounds in the presence of catalytic amounts of GaÂ(OTf)<sub>3</sub>. This gives rise to the formation of tetrazolothione moieties
in an atom-economical manner. Mechanistically, we have determined
that this transformation may occur by kinetically favored hydrothiolation,
followed by rearrangement to the observed hydroamination products
Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
General
control nonderepressible 2 (GCN2) protein kinase is a cellular
stress sensor within the tumor microenvironment (TME), whose signaling
cascade has been proposed to contribute to immune escape in tumors.
Herein, we report the discovery of cell-potent GCN2 inhibitors with
excellent selectivity against its closely related Integrated Stress
Response (ISR) family members heme-regulated inhibitor kinase (HRI),
protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase
(PERK), as well as good kinome-wide selectivity and favorable PK.
In mice, compound 39 engages GCN2 at levels ≥80%
with an oral dose of 15 mg/kg BID. We also demonstrate the ability
of compound 39 to alleviate MDSC-related T cell suppression
and restore T cell proliferation, similar to the effect seen in MDSCs
from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI)
as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced
by treatment with compound 39 demonstrating the complementarity
of these two mechanisms
Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
General
control nonderepressible 2 (GCN2) protein kinase is a cellular
stress sensor within the tumor microenvironment (TME), whose signaling
cascade has been proposed to contribute to immune escape in tumors.
Herein, we report the discovery of cell-potent GCN2 inhibitors with
excellent selectivity against its closely related Integrated Stress
Response (ISR) family members heme-regulated inhibitor kinase (HRI),
protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase
(PERK), as well as good kinome-wide selectivity and favorable PK.
In mice, compound 39 engages GCN2 at levels ≥80%
with an oral dose of 15 mg/kg BID. We also demonstrate the ability
of compound 39 to alleviate MDSC-related T cell suppression
and restore T cell proliferation, similar to the effect seen in MDSCs
from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI)
as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced
by treatment with compound 39 demonstrating the complementarity
of these two mechanisms