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. 2022 Jul 28;65(14):9678-9690.
doi: 10.1021/acs.jmedchem.2c00741. Epub 2022 Jul 14.

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction

John M Ketcham  1 , Jacob Haling  1 , Shilpi Khare  1 , Vickie Bowcut  1 , David M Briere  1 , Aaron C Burns  1 , Robin J Gunn  1 , Anthony Ivetac  1 , Jon Kuehler  1 , Svitlana Kulyk  1 , Jade Laguer  1 , J David Lawson  1 , Krystal Moya  1 , Natalie Nguyen  1 , Lisa Rahbaek  1 , Barbara Saechao  1 , Christopher R Smith  1 , Niranjan Sudhakar  1 , Nicole C Thomas  1 , Laura Vegar  1 , Darin Vanderpool  1 , Xiaolun Wang  1 , Larry Yan  1 , Peter Olson  1 , James G Christensen  1 , Matthew A Marx  1
Affiliations

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction

John M Ketcham et al. J Med Chem. .

Abstract

SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRASG12C protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRASG12C, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRASG12C. 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:KRASG12C 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 tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.

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Conflict of interest statement

The authors declare the following competing financial interest(s): All authors of this manuscript are employees of Mirati Therapeutics.

Figures

Figure 1
Figure 1
Comparison of representative SOS1 literature compounds and erlotinib.
Figure 2
Figure 2
Design concept for phthalazine-based inhibitors of the SOS1:KRAS PPI leading to MRTX0902.
Figure 3
Figure 3
(a) Modeled structure of 11 bound to SOS1 (b) Modeled structure of 12 bound to SOS1 (modeled with PDB 5OVI).
Figure 4
Figure 4
X-ray co-crystal structure of 15 bound to SOS1 (PDB 7UKS).
Figure 5
Figure 5
pERK modulation in tumors from mice dosed orally with compound 24, MRTX849, and their combination. “#” indicates drug treated-tumor pERK levels were significantly different compared to vehicle-treated cohorts by two-tailed Student’s t test (GraphPad Prism v.8.2.0; p-value < 0.05). “*” indicates drug treated-tumor pERK levels were significantly different compared to MRTX849-treated cohorts by two-tailed Student’s t test (GraphPad Prism v.8.2.0; p-value < 0.05).
Figure 6
Figure 6
X-ray co-crystal structure of MRTX0902 (32) (PDB 7UKR).
Figure 7
Figure 7
MRTX0902 (32) in vivo efficacy and PD in the MIA PaCa-2 mouse model.
Scheme 1
Scheme 1. Synthesis of MRTX0902 (32)
Reagents and conditions: (a) 1-(vinyloxy)butane, P(t-Bu)3Pd G2, N,N-dicyclohexylamine, dioxane, 85 °C, 10 h, then 4 N HCl, 40 °C, 2 h; (b) hydrazine monohydrate, EtOH, 70 °C, 10 h, 76% yield (over 2 steps); (c) 12 N HCl, 80 °C, 6 h; (d) POCl3, 100 °C, 5 h, 63% yield (over 2 steps); (e) (R)-3-(1-aminoethyl)-2-methylbenzonitrile, CsF, DMSO, 130 °C, 2 h, 43% yield; (f) morpholine, 110 °C, 1 h, 88% yield.
See this image and copyright information in PMC

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