MRTX1133 is a noncovalent, potent, and selective KRAS G12D inhibitor. MRTX1133 optimally fills the switch II pocket and extends three substituents to favorably interact with the protein, resulting in an estimated K D against KRAS G12D of 0.2 pM. MRTX1133 prevents SOS1-catalyzed nucleotide exchange and/or formation of the KRAS G12D/GTP/RAF1 complex, thereby inhibiting mutant KRAS-dependent signal transduction. MRTX1133 selectively inhibits KRAS G12D mutant, but not KRAS wild-type, tumor cells. MRTX1133 has single digit nanomolar activity in cellular assays and marked in vivo efficacy in tumor models harboring KRAS G12D mutations In Vitro MRTX1133 inhibits ERK phosphorylation in the AGS cell line with an IC 50 ranging 1-10 nM (AsPC-1, Panc 04.03, Panc 02.03, SW1990, GP2D, Suit2, A427, SNU1033, and HPAC cells). In a 2D viability assay, the IC 50 of MRTX1133 is 6 nM against AGS cells (KRAS G12D), while demonstrating more than 500-fold selectivity against MKN1, a cell line which is dependent on KRAS for its growth and survival due to the amplification of wild-type KRAS. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo MRTX1133 displays efficacious in a KRAS G12D mutant xenograft mouse tumor model . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: 6-8-weekold, female, athymic nude-Foxn1 nu mice (Panc 04.03 model) Dosage: 3, 10, or 30 mg/kg Administration: Intraperitoneal; twice a day for 28 days Result: An antitumor efficacy study in this model resulted in MRTX1133 dose-dependent antitumor activity with 94% growth inhibition observed at 3 mg/kg BID (IP) and tumor regressions of -62% and -73% observed at 10 and 30 mg/kg BID (IP), respectively. Form:Solid IC50& Target:KRas G12D 0.2 pM (Kd)