MRTX1133

However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer...Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

As a proof of concept, we identify two new, drug-like small molecules with the new method; these compounds specifically inhibit the growth of the PANC-1 cell line with KRAS mutation G12D in vitro and in vivo. Importantly, the two new compounds show significantly lower IC50 and higher specificity against the G12D KRAS mutant human pancreatic cancer cell line PANC-1, as compared to the recently described selective G12D KRAS inhibitor MRTX-1133.

Further investigation of the immunological response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of PDAC patients.

Herein, we report the design, synthesis, and biological evaluation of a series of KRAS PROTACs by connecting the analogues of MRTX1133 and the VHL ligand...This compound selectively and potently suppressed the growth of multiple KRAS mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRAS-driven cancers as the complementary therapeutic strategy to KRAS inhibition.

The results obtained in this work showed a profound inhibition of tumor growth, which was associated with a reduction in cell proliferation, an increase in apoptosis, and a reduction in the MAPK and PI3K/AKT/mTOR signaling pathways. In conclusion, these results demonstrate the high potency and efficacy of MRTX1133 in KRAS-PMP tumors and provide a rationale for clinical trials.

At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.

These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high in vitro and in vivo potency of these new inhibitors call for further profiling.

The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. Additionally, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bring about a paradigm shift in its management.

The combination of MRTX1133 and cetuximab serves as a potential and promising therapeutic approach for colorectal cancer with KRAS mutation. KRAS is a frequent genetic mutation not only in colorectal cancer, but also in pancreatic and lung cancer, and the results of this study open new avenues for potential treatment of many cancer patients.

Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.

Mechanistically, inhibition of KRAS in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8 T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.

MRTX1257 predominantly reduced proliferation of XG7 cells, whereas MRTX1133 led to potent cell death induction of KARPAS620 and KP6 cells. Combinations of MRTX1257 with investigational or established anti-MM drugs, including melphalan, bortezomib or pomalidomide, led to no antagonism and in some cases – including combination with MEKi trametinib – caused supra-additive effects... This study documents mutant-specific activity of KRAS G12C and G12D inhibitors in MM cells and provides functional insights into the pharmacological inhibition of KRAS in MM. Ongoing in vitro and in vivo studies are examining the targeting of genes/pathways associated with escape from KRAS inhibition, as a framework for future efforts to improve the rates, depth and durability of responses to KRAS inhibition in MM.

The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking...In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-X-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo...This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.

Blockade of activated EGFR with clinically used antibodies or kinase inhibitors suppressed the EGFR/wild-type RAS signaling axis, sensitized MRTX1133 monotherapy, and caused the regression of KRAS-mutant CRC organoids and cell line-derived xenografts. Overall, this study uncovers feedback activation of EGFR as a prominent molecular event that restricts KRAS inhibitor efficacy and establishes a potential combination therapy consisting of KRAS and EGFR inhibitors for patients with KRAS-mutated CRC.

Our studies reveal strong synergy between MRTX1133 & 5-FU in human pancreatic & colon cancer models at much lower than IC50 dosage which is important for avoiding side effects. This is the first description that effect of KRAS G12D inhibitor MRTX1133 is active on KRAS G12V. The surprising synergy in KRAS G12V samples with combination therapy and the important synergistic change in cytokine patterns suggests potential strong immune stimulatory anti-cancer effects of MRTX1133 & 5FU against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation which should be considered when including patients with respective mutations in clinical trials.

Additionally, more CD8+ T cells in the tumor-draining lymph nodes of MRTX1133-treated mice were IFNγ+ (P < 0.001), illustrating a systemic immune effect from MRTX1133. Our findings indicate that T cells play an important role in MRTX1133’s demonstrated efficacy, suggesting a “vaccine effect” from mutant KRAS inhibition and offering a rationale for testing novel combinations of mutant KRAS inhibitors with cancer immunotherapies.

P1/2, N=304, Recruiting, Mirati Therapeutics Inc. | Not yet recruiting --> Recruiting

P1/2, N=304, Not yet recruiting, Mirati Therapeutics Inc.

Recent breakthroughs in the development of mutant-specific KRAS inhibitors include the FDA approved drug Lumakras (Sotorasib, AMG510) for KRAS G12C-mutated non-small cell lung cancer (NSCLC), and MRTX1133, a promising clinical candidate for the treatment of KRAS G12D-mutated cancers. The most promising hit, UNC10104889, was further investigated through a structure activity relationship (SAR)-by-catalog approach in an attempt to improve potency and circumvent solubility liabilities. Overall, we present the TR-FRET platform as a robust assay to screen fast-cycling KRAS mutants enabling future discovery efforts for novel chemical probes and drug candidates.

Nevertheless, significant progress is now being made in the G12D space with the development of several compounds that can bind to and inhibit KRAS G12D, most notably MRTX1133. Exciting advances in this field also include an immunotherapeutic approach that uses adoptive T-cell transfer to specifically target G12D in pancreatic cancer. In this mini-review, we discuss recent advances in KRAS G12D targeting and the potential for further clinical development of the various approaches.

T cells were necessary for MRTX1133's full anti-tumor effect, and T cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.

The covalent KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are used to treat patients with KRAS-G12C-mutated non-small cell lung cancer. Recently, through extensive structure-based drug design from Mirati Therapeutics, a novel non-covalent KRAS-G12D inhibitor, MRTX1133, showed significant preclinical antitumor activity in KRAS-G12D-bearing tumor cells, especially pancreatic ductal adenocarcinoma. Here, we discuss the selectivity, efficacy, toxicity, and potential application challenges of this novel targeted protein inhibitor.

Informed by the structure of the KRAS inhibitor adagrasib, Hallin et al have now, through multiple rounds of structure-based drug design, identified and validated a potent, selective, and non-covalent KRAS inhibitor, MRTX1133. This study demonstrated that MRTX1133 inhibited both the inactive and active state of KRAS and showed potent anti-tumor activity in several pre-clinical models of pancreatic and colorectal cancer, especially when combined with cetuximab, a monoclonal antibody against the EGFR, or BYL-719, a potent PI3Kα inhibitor.

Pharmacophore-based virtual screening based on the structural binding mechanisms of MRTX1133 identified ZINC78453217, ZINC70875226 and ZINC64890902 as potential KRAS inhibitors. Further, structural optimisations and biochemical testing of these compounds would assist in the discovery of effective KRAS inhibitors.

In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS inhibitor...Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS mutation-positive tumors on mutant KRAS for tumor cell growth and survival.

Similar to what was seen in a targeted genetic screen with our selective KRASG12C inhibitor MRTX849, several genes that act either upstream or downstream of KRAS were depleted with MRTX1133 treatment which illuminate specific targetable vulnerabilities in the context of KRASG12D inhibition. Further evaluation of dependencies utilizing an integrated analysis of RNAseq data also revealed KRAS regulates and is critically dependent on pro-survival and cell cycle genes for cancer cell viability. These data lend further insight into tumor response to KRASG12D inhibition and provide key insight into the genes that mediate the mechanism of action of, as well as confer partial resistance to MRTX1133, and identify combination targets that can augment the anti-tumor effect of MRTX1133.

Our study suggests that pre-existing heterogeneous subclones with epigenetic plasticity contribute to escaping direct KRAS inhibition in pancreatic cancer and provides a new avenue to overcome such resistance by combining KRAS inhibitors with BET inhibitors.

However, when compared to KRAS, selective inhibition of KRAS presents a significant challenge due to the requirement of inhibitors to bind KRAS 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 KRAS inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRAS mutant xenograft mouse tumor model.