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. 2025 Aug 14;68(15):15649-15668.
doi: 10.1021/acs.jmedchem.5c00576. Epub 2025 Jul 25.

Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy

Joachim Bröker  1 , Alex G Waterson  2 , Timothy R Hodges  2 , Jason R Abbott  2 , Allison Arnold  2 , Jark Böttcher  1 , Nina Braun  1 , Jianwen Cui  2 , Julian E Fuchs  1 , Thomas Gerstberger  1 , Sebastian Gogg  1 , Sabine Hanner  1 , Lorenz Herdeis  1 , Lucas W Howell  2 , Andreas Mantoulidis  1 , Moriz Mayer  1 , Jason Phan  2 , Francesca Rocchetti  1 , Kyra Sankar  1 , Dhruba Sarkar  2 , Otmar Schaaf  1 , John L Sensintaffar  2 , Qi Sun  2 , Tobias Wunberg  1 , Stephen W Fesik  2
Affiliations

Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy

Joachim Bröker et al. J Med Chem. .

Abstract

KRAS is one of the most highly validated cancer targets. Here we describe the design and synthesis of two reversible pan-KRAS inhibitors, BI-2865 and BI-2493. From our KRASG12C inhibitor program, we identified BI-2865, a potent noncovalent KRAS inhibitor that showed cellular activity against a broad spectrum of KRAS alleles and selectivity against HRAS and NRAS. Spirocyclization led to the discovery of BI-2493, a highly rigid analogue exhibiting better potency, metabolic stability, and permeability. BI-2493 shows in vivo efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization.

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Figures

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1
Structure of 1 in complex with GDP-KRAS (PDB Code 9IAP, ligand color-coded by atom type in green, water molecules are shown as red spheres, hydrogen bonds as blue dotted lines).
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Interactions of the His95/Glu62/Asp92 subpocket as observed in the GDP-KRAS structures in complex with 5 (a), 10 (b), 12 (c) and 14 (d) (PDB Codes: 9IAW, 9IAY, 9IB4, and 8AZV) (ligands color-coded by atom type in cyan, pink, yellow and orange, respectively, water molecules are shown as red spheres, hydrogen bonds as blue dotted lines).
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Superposition of the GDP-KRAS structures in complex with 5 (cyan) and 18 (violet) (PDB codes 9IAW and 9IB5, ligands color-coded by atom type, water molecules are shown as red spheres, hydrogen bonds as blue dotted lines). Protein and water is only shown for 18.
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Smiles rearrangement observed for N–H prolinols.
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Pan-KRAS inhibitor BI-2493 (18) shows potent antiproliferative effects on KRAS dependent cell lines and weaker effects on HRAS and NRAS dependent cells, For EC50 values, see Table S6. (A) Isogenic BaF3 cells expressing the indicated RAS isoforms and mutants were treated for 72 h in the absence of IL3 (oncogene dependent growth) to determine the effect on proliferation (mean ± SEM, n = 3). (B) Cancer cell lines harboring different KRAS isoforms as well as a control cell line (A-375) were treated for 120 h to determine the effect on proliferation (mean ± SEM, n = 3).
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BI-2493 (18) suppresses tumor growth in xenograft models driven by different KRAS mutant proteins. (a) Antitumor activity of BI-2493 in the SW480 (KRASG12V) colorectal cancer xenograft model. BI-2493 was administered orally twice daily at 30 or 90 mg/kg. Data represent the mean tumor volume ± SEM (n = 7). (b) % Body weight change of mice in (a). Data represent the mean % body weight change ± SEM (n = 7). (c) Antitumor activity of BI-2493 in the NCI-H358 (KRASG12C) nonsmall cell lung cancer xenograft model. BI-2493 was administered orally twice daily at 30 mg/kg. Data are presented as mean ± SEM (n = 8). (d) % Body weight change of mice in (c).
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1. Synthesis of Phenyl Oxadiazole 1
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2. Synthesis of Pyridyl Oxadiazoles 2–3
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3. Synthesis of Pyrimidyl Oxadiazoles 5–13
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4. Synthesis of Ethyl Analogue 15
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5. Synthesis of Isoxazole 16
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6. Synthesis of First Spiro Isoxazole 17 via Racemic Spiro Ketal 46
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7. Observed Intermediates in the Conversion of 46a towards Isoxazoles 51 and 54
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8. Synthesis of Diastereopure Spiro Isoxazoles 17a–21 from Enantiopure Spiro Ketal 46a
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