Process Development and Scale-Up of the SOS1 Inhibitor MRTX0902

Scattolin, Thomas; Lizza, Joseph R.; Xu, Zhou; Zhao, Decai; Chen, Cheng‐yi

doi:10.1021/acs.oprd.3c00030

Cited by 3 publications

(4 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For a final refinement of the reaction conditions, the more complex model derived from the synthesis of MRTX0902, ketimine 7 , was chosen to increase the dynamic range of the reaction. A series of reactions exploring other fluoride salts, reagent equivalency, solvents, reaction scale, and controls were examined (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…In our research to discover novel therapeutics targeting oncogenic drivers of cancer we have encountered multiple bioactive chemical series that required a chiral benzylamine element . For example, we developed MRTX0902, a potent, selective, and metabolically stable, clinical-stage inhibitor of the son of sevenless 1 (SOS1):KRAS protein–protein interaction (PPI). , Over the course of the design and discovery program of SOS1:KRAS PPI inhibitors ( 1 , Figure A), many diverse enantiopure benzylamine fragments were prepared for attachment onto to the phthalazine core (2).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride

Aloiau,

Bobek,

Pearson

et al. 2024

J. Org. Chem.

View full text Add to dashboard Cite

In our drug discovery campaigns to target the oncogenic drivers of cancers, the demand for a chemoselective, stereoselective and economical synthesis of chiral benzylamines drove the development of a catalytic zirconium hydride reduction. This methodology uses the inexpensive, bench stable zirconocene dichloride, and a novel tetrabutylammonium fluoride activation tactic to catalytically generate a metal hydride under ambient conditions. The diastereo-and chemoselectivity of this reaction was tested with the preparation of key intermediates from our discovery programs and in the scope of sulfinyl ketimines and carbonyls relevant to medicinal chemistry and natural product synthesis. A preliminary mechanistic investigation conducted into the role of tetrabutylammonium fluoride indicates that formation of a zirconocene fluoride occurs to initiate catalysis. The implications of this convenient activation approach may provide expanded roles for zirconium hydrides in catalytic transformations.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride

Aloiau,

Bobek,

Pearson

et al. 2024

J. Org. Chem.

View full text Add to dashboard Cite

show abstract

“…In our own research to develop novel therapies targeting oncogenic drivers of cancer, we have encountered pharmacophores that include a chiral benzylamine element . Recently, we developed MRTX0902 , a potent, selective, and metabolically stable clinical-stage inhibitor of the Son of Sevenless 1 (SOS1): KRAS protein–protein interaction (PPI) . It is hypothesized that blocking this PPI will increase the available concentration of GDP-bound KRAS protein for selective switch-II KRAS binders to inhibit, thereby potentially increasing the effectiveness of pharmaceutical agents such as adagrasib and sotorasib, which covalently bind KRAS G12C in the GDP-bound state .…”

Section: Introductionmentioning

confidence: 99%

“… 10 Recently, we developed MRTX0902 , a potent, selective, and metabolically stable clinical-stage inhibitor 11 of the Son of Sevenless 1 (SOS1): KRAS protein–protein interaction (PPI). 12 It is hypothesized that blocking this PPI will increase the available concentration of GDP-bound KRAS protein for selective switch-II KRAS binders to inhibit, thereby potentially increasing the effectiveness of pharmaceutical agents such as adagrasib and sotorasib, which covalently bind KRAS G12C in the GDP-bound state. 13 During the design and discovery of MRTX0902 , currently in phase 1 studies, the benzylamine motif proved to be a critical structural element.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

Aloiau,

Bobek,

Caddell Haatveit

et al. 2024

J. Org. Chem.

View full text Add to dashboard Cite

Chiral amine synthesis remains a significant challenge in accelerating the design cycle of drug discovery programs. A zirconium hydride, due to its high oxophilicity and lower reactivity, gave highly chemo-and stereoselective reductions of sulfinyl ketimines. The development of this zirconocene-mediated reduction helped to accelerate our drug discovery efforts and is applicable to several motifs commonly used in medicinal chemistry. Computational investigation supported a cyclic half-chair transition state to rationalize the high selectivity in benzyl systems.

show abstract

The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading

Sudhakar,

Yan,

Qiryaqos

et al. 2024

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the RTK/MAPK pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of twelve KRAS G12C-mutant human non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1, PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy.

show abstract

Process Development and Scale-Up of the SOS1 Inhibitor MRTX0902

Cited by 3 publications

References 6 publications

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading

Contact Info

Product

Resources

About