Krazati (adagrasib)

Several compounds, including Pirbuterol, Levonordefrin, Mugineic acid, Irilin D, DH-DMX, and DXP, demonstrated favorable binding affinities relative to reference inhibitors MRTX1133, Daraxonrasib, and Adagrasib. Notably, Levonordefrin showed consistent binding across multiple KRAS variants. These findings identify potential candidates for further experimental validation and support the application of computational approaches in KRAS-targeted drug discovery for Pancreatic cancer.

P1/2, N=12, Completed, Verastem, Inc. | N=85 --> 12 | Trial completion date: Jan 2026 --> Jun 2026 | Trial primary completion date: Dec 2025 --> Jun 2026 | Active, not recruiting --> Completed

Herein we outline the biology and epidemiology of KRAS alterations at the lineage and allele levels, reviewing the clinical evidence for KRASG12C inhibition from the discovery of the recessive switch pocket to sotorasib, adagrasib and other novel molecules, and extending to the non-KRASG12C era, including RAS (ON)- and KRASG12D-selective strategies and early efficacy signals. We propose a 'three-clock, two-window' framework, which includes half-life exposure, occupation retention and extracellular signal-regulated kinase (ERK) rebound calibration of dosing rhythm; a vascular normalization window and an immune/myeloid plasticity window to achieve longitudinal Src homology 2-containing protein tyrosine phosphatase 2/son of sevenless homologue 1 and transverse epidermal growth factor receptor, phosphoinositide 3-kinase-protein kinase-mammalian target of rapamycin synergy. At the same time, we construct and propose a closed loop of exposure, occupation, pathway inhibition, circulating tumour DNA (ctDNA) and imaging by utilizing ctDNA dynamics, phosphorylated ERK rebound and perfusion imaging, as well as myeloid lineage quantification, to improve durable inhibition and overall survival through time-aligned combined effects.

Allele-specific KRAS inhibitors such as the KRASG12C inhibitors sotorasib and adagrasib have demonstrated clinical activity as monotherapy but adaptive signaling in response to KRAS pathway inhibition can promote resistance and limit the efficacy of these drugs. Using xenograft models, we observed that pharmacologic blockade of FAK enhanced the anti-tumor activity of KRAS inhibitors. These data highlight the therapeutic potential of FAK/SRC inhibitors to mitigate adaptive signaling induced by KRAS inhibition and enhance the clinical activity of KRAS inhibitors.

P2, N=90, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2026 --> Sep 2026

Competition with MRTX849 blocked KRAS degradation, supporting on-target covalent engagement at Cys12. These findings establish carborane as a compact, functional HyT that drives proteasome-dependent degradation of endogenous KRASG12C and suppresses downstream signaling, broadening degrader design to include an E3-independent modality for the degradation of oncogenic proteins.

P3, N=338, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Sep 2027 --> May 2026

Although recent advances have led to covalent inhibitors such as Sotorasib and Adagrasib for the KRAS G12C mutation, effective therapies for other common variants, particularly KRAS G12D, which is highly prevalent in aggressive pancreatic cancers, remain limited...To further validate the predictive capability of the models, two compounds identified as high-confidence candidates, Cobimetinib and Etrasimod, were selected for experimental evaluation...While additional biochemical and pathway-level studies are required to confirm direct target engagement, these results support the model's utility in prioritizing candidate compounds with allele-specific activity profiles. Overall, this study provides a data-driven framework for identifying potential KRAS-targeted therapies and highlights the value of integrating machine learning predictions with experimental validation.

JMKX1899 selectively inhibited cell viability across multiple KRAS G12C-mutant cell lines, exhibiting slightly greater potency than AMG510 and MRTX849. Early clinical data from KRAS G12C-mutant NSCLC patients with BM treated by JMXK1899 further confirm its blood-brain barrier penetration and antitumor activity. These findings strongly support the continued clinical development of JMKX1899 as a promising therapeutic candidate for NSCLC patients with KRAS G12C mutations and BM.

Mutant-specific KRAS G12C inhibitors have shown promising therapeutic efficacy, leading to FDA approval of sotorasib and adagrasib, although their use is limited to patients with the relatively rare G12C KRAS mutation...While just a few years ago, pan-RAS inhibitors were predicted to be severely toxic or even fatal, the apparent safety profile of RMC-6236 (daraxonrasib), a pan-RAS inhibitor currently in clinical trials, suggests otherwise. Indeed, pan-RAS inhibitors are now considered by many in the RAS field to be the most promising class in development. In this review, we summarize the evolution and current status of pan-RAS and pan-KRAS inhibitors in preclinical and clinical development and highlight emerging human-relevant tumor models that are advancing preclinical evaluation.

KRAS G12C-mutant non-small cell lung cancer (NSCLC) has transitioned from a therapeutically problematic disease to a precision-targetable cancer, anchored by the landmark approvals of sotorasib and adagrasib. We further highlight patient-derived 3D models, multi-omics technologies, and ctDNA-guided monitoring as essential translational platforms. Finally, we propose an integrated translational roadmap that combines mechanistic insights with clinical innovation, offering new directions for precision therapy and improved patient outcomes in KRAS-driven NSCLC.

Adagrasib with ICI improved long-term survival and blocked CNS progression in dual extra- and intracranial BM models.  These findings support investigation of adagrasib with ICI in patients with KRASG12C-mutant BM.