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. 2018 Nov 7;9(12):1230-1234.
doi: 10.1021/acsmedchemlett.8b00382. eCollection 2018 Dec 13.

Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity

Jay B Fell  1 , John P Fischer  1 , Brian R Baer  1 , Joshua Ballard  1 , James F Blake  1 , Karyn Bouhana  1 , Barbara J Brandhuber  1 , David M Briere  2 , Laurence E Burgess  1 , Michael R Burkard  1 , Harrah Chiang  2 , Mark J Chicarelli  1 , Kevin Davidson  1 , John J Gaudino  1 , Jill Hallin  2 , Lauren Hanson  1 , Kenneth Hee  1 , Erik J Hicken  1 , Ronald J Hinklin  1 , Matthew A Marx  2 , Macedonio J Mejia  1 , Peter Olson  2 , Pavel Savechenkov  1 , Niranjan Sudhakar  2 , Tony P Tang  1 , Guy P Vigers  1 , Henry Zecca  1 , James G Christensen  2
Affiliations

Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity

Jay B Fell et al. ACS Med Chem Lett. .

Abstract

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Reactants
(a) Cbz-piperazine, Cs2CO3, DMA, 150 °C, 95%. (b) TFA, DCM, 95%. (c) NaOtBu, BINAP/Pd2DBA3, toluene, 100 °C, 24 h, 33%. (d) Pd/C, H2, MeOH, 69%. (e) Acryloyl chloride, Hunig’s base, DCM, 19%.
Figure 1
Figure 1
X-ray crystal structure of 4 in complex with KRAS-G12C at 1.8 Å resolution. Hydrogens are added for clarity (PDB ID 6N2J).
Figure 2
Figure 2
X-ray crystal structure of compound 12 bound to KRAS-G12C with 1.7 Å resolution. Hydrogens added for clarity (PDB ID 6N2K).
Figure 3
Figure 3
Antitumor efficacy of compound-13-dosed IP in the MIA PaCa-2 tumor xenograft model. The mean tumor volume for 12 tumors is plotted, and the error bars represent the standard error of the mean.
Figure 4
Figure 4
KRAS-G12C target engagement in MIA PaCa-2 tumors. The mean % KRAS-G12C engagement (see the Supporting Information) for three tumors is plotted, and the error bars represent the standard deviation.
See this image and copyright information in PMC

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