Discovery Of A Potent Selective And Orally Bioavailable Sos1 In this report, we detail the design and discovery of mrtx0902─a potent, selective, brain penetrant, and orally bioavailable sos1 binder that disrupts the sos1:kras g12c ppi. oral administration of mrtx0902 in combination with mrtx849 results in a significant increase in antitumor activity relative to that of either single agent, including. Highly selective for sos1 and show no activity against egfr. our work has led to the identificationof the clinical candidate mrtx0902, a potent and orally bioavailable inhibitor of the sos1:kras complex that exhibits complete tumor regressions in mouse models when administered in combination with sub maximal doses of our krasg12c inhibitor.
Pdf Design And Discovery Of Mrtx0902 A Potent Selective Brain Through rational design, we have discovered mrtx0902 ̶a potent, selective, and orally bioavailable inhibitor of sos1 that is brain penetrant. mrtx0902 in combination with our krasg12c inhibitor mrtx849 yields enhanced mapk pathway inhibition and complete tumor regression in the krasg12c mia paca 2 model. mrtx0902 is currently in ind enabling. Rgt 018 concentration (μm) figure 1. (a) biochemical characterization of rgt 018 was carried out through the analysis of interaction assays using sos1 and sos2 recombinant proteins with krasg12d or krasg12c mutants. (b) rgt 018 was tested in a panel of 330 kinases by kinome wide panel (kwp) service to determine the inhibition of kinase activity. Here we describe the preclinical profile of a potent, selective, and orally bioavailable in vivo tool compound, rm 023, which disrupts the critical interaction between kras and sos1. by preventing formation of the kras sos1 complex, these inhibitors block reloading of kras with gtp, and thereby inhibit ras pathway signaling and ras driven. Rgt 018, a potent and selective sos1 inhibitor, was identified with optimal drug like properties. in vitro, rgt 018 blocked the interaction of kras:sos1 with single digit nm potency and is highly selective against sos2. rgt 018 inhibited kras signaling and the proliferation of a broad spectrum of kras driven cancer cells as a single agent in vitro.
Figure 2 From Design And Discovery Of Mrtx0902 A Potent Selective Here we describe the preclinical profile of a potent, selective, and orally bioavailable in vivo tool compound, rm 023, which disrupts the critical interaction between kras and sos1. by preventing formation of the kras sos1 complex, these inhibitors block reloading of kras with gtp, and thereby inhibit ras pathway signaling and ras driven. Rgt 018, a potent and selective sos1 inhibitor, was identified with optimal drug like properties. in vitro, rgt 018 blocked the interaction of kras:sos1 with single digit nm potency and is highly selective against sos2. rgt 018 inhibited kras signaling and the proliferation of a broad spectrum of kras driven cancer cells as a single agent in vitro. We report the discovery of a highly potent, selective and orally bioavailable small molecule sos1 inhibitor, bi 3406, that binds to the catalytic domain of sos1 thereby preventing the interaction with kras. bi 3406 reduces formation of gtp loaded ras and limits cellular proliferation of a broad range of kras driven cancers. Design and discovery of mrtx0902, a potent, selective, brain penetrant, and orally bioavailable inhibitor of the sos1:kras protein protein interaction.
Table 1 From Design And Discovery Of Mrtx0902 A Potent Selective We report the discovery of a highly potent, selective and orally bioavailable small molecule sos1 inhibitor, bi 3406, that binds to the catalytic domain of sos1 thereby preventing the interaction with kras. bi 3406 reduces formation of gtp loaded ras and limits cellular proliferation of a broad range of kras driven cancers. Design and discovery of mrtx0902, a potent, selective, brain penetrant, and orally bioavailable inhibitor of the sos1:kras protein protein interaction.
Discovery Of An Orally Bioavailable And Selective Pkmyt1 Inhibitor Rp
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