4 research outputs found
Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma
Abrogation of errant signaling along
the MAPK pathway through the
inhibition of B-RAF kinase is a validated approach for the treatment
of pathway-dependent cancers. We report the development of imidazo-benzimidazoles
as potent B-RAF inhibitors. Robust <i>in vivo</i> efficacy
coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and
PD-efficacy relationships led to the identification of RAF265, <b>1</b>, which has advanced into clinical trials
Design, Structure–Activity Relationship, and in Vivo Characterization of the Development Candidate NVP-HSP990
Utilizing
structure-based drug design, a novel dihydropyridopyrimidinone
series which exhibited potent Hsp90 inhibition, good pharmacokinetics
upon oral administration, and an excellent pharmacokinetic/pharmacodynamic
relationship in vivo was developed from a commercial hit. The exploration
of this series led to the selection of NVP-HSP990 as a development
candidate
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