Substituted Tetrahydropyrrolo[2,1-<i>b</i>]oxazol-5(6<i>H</i>)-ones and Tetrahydropyrrolo[2,1-<i>b</i>]thiazol-5(6<i>H</i>)-ones as Hypoglycemic Agents

A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies

Discovery of 5‑Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors

SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile

Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS^G12D Inhibitor

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model

Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS^G12D Inhibitor

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model

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

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

Supplementary Data from The KRAS^G12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients

Supplementary methods and Tables</p

Supplementary Data from The KRAS^G12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients

Supplementary Table S8</p

Supplementary Data from The KRAS^G12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients

Supplementary Table S7</p

Identification of the Clinical Development Candidate <b>MRTX849</b>, a Covalent KRAS^G12C Inhibitor for the Treatment of Cancer

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target’s resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described

The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients

We directly interrogated the role of selected genes in mediating therapeutic response to MRTX849 utilizing a focused CRISPR/Cas9 knockout screen targeting approximately 400 genes including many genes involved in KRAS signaling. This was conducted in H358 and H2122 cells in vitro and in H2122 xenografts in vivo in presence and absence of MRTX849 treatment. Three independent drug anchored CRISPR studies were performed and two data files have been provided for each study. The .csv metadata files contain sample IDs, replicate number, sample descriptions and various experimental conditions. The .xlsx data files contain guide labels, guide sequences and NGS guide counts.Three independent drug anchored CRISPR studies were performed and two data files have been provided for each study. The .csv metadata files contain sample IDs, replicate number, sample descriptions and various experimental conditions. The .xlsx data files contain guide labels, guide sequences and NGS guide counts.</p