Year-End Sale is Live! Find Exclusive Prices on the Best Selling Pharma & MedTech Reports. Check Now!
Apr 05, 2024
KRAS mutations represent the most commonly encountered driver oncogene, implicated in approximately 25% of all human cancers, with KRASG12D emerging as a predominant isoform, particularly prevalent in pancreatic, colorectal, and non-small cell lung cancers. Despite its frequency, targeting KRASG12D poses distinct challenges due to the absence of a reactive amino acid residue for irreversible inhibitory modification by a ligand.
In pancreatic cancer, KRASG12D is detected in approximately 35% of cases, while in colorectal and non-small cell lung cancers, its prevalence stands at 13% and 5%, respectively. Although less common in other cancers, KRASG12D mutations remain a significant therapeutic target.
Historically considered ‘undruggable’, the landscape shifted with the approval of sotorasib, the first KRASG12C inhibitor in 2021. However, the majority of clinical-stage KRAS inhibitors are tailored towards KRASG12C, leaving a critical gap for targeting other mutations like KRASG12D, which is prevalent across various cancers. The urgent need persists for effective therapies targeting KRASG12D to address the diverse oncological landscape and improve patient outcomes.
Article in PDF
The landscape is evolving rapidly, with increasing attention and investment in G12D-selective projects. As evidenced by preclinical data presented at AACR Annual Meeting 2024, there is a growing interest in developing therapies specifically tailored to target KRASG12D. Key players such as Tyligand Bioscience, Lilly, Verastem, and GenFleet are at the forefront of this endeavor, contributing to the expanding arsenal of KRAS inhibitors.
TSN1611, a selective inhibitor targeting KRASG12D, has demonstrated remarkable potential in preclinical studies. It exhibits exceptional selectivity and activity both in vitro and in vivo, along with favorable pharmacokinetic properties, oral bioavailability, and the ability to penetrate the brain. Its safety profile, supported by preclinical data, positions it favorably for further advancement.
Notably, TSN1611 effectively inhibits both active and inactive forms of the KRASG12D protein, showcasing impressive potency with IC50 values of 1.23 and 1.49 nM, respectively. Its direct binding to KRASG12D protein is characterized by a KD value of 1.93 pM in SPR assay. TSN1611 demonstrates potent anti-proliferation activity against various tumor cell lines carrying the KRASG12D mutation while maintaining selectivity over other RAS isoforms.
The recent FDA clearance of an oral formulation of TSN1611 for clinical trials marks a significant milestone, with a Phase I/II study set to commence in the first half of 2024 pending regulatory submission and review. This underscores the growing momentum behind TSN1611 as a promising therapeutic candidate.
TSN1611 stands out due to its unique structural advantages and superior toxicity profile compared to similar compounds. With its potential to emerge as a leading pipeline product globally for targeting KRASG12D, TSN1611 holds promise as a transformative therapy in oncology.
Lilly’s LY3962673 has exhibited potent inhibition of KRASG12D, displaying selectivity against wild-type KRAS in both cell lines and in vivo models. The mechanism of action involves non-covalent binding to KRASG12D-GDP with a high affinity (Kd 0.071 nM), compared to KRASG12D-GTPγS (Kd 26.7 nM).
In a diverse panel of cancer cell lines, LY3962673 selectively suppressed MAPK signaling and hindered the growth of KRASG12D mutant cells while sparing wild-type KRAS and non-G12D mutant cells. Sensitivity to LY3962673 varied among KRASG12D-mutant cells, indicating differences in dependence on KRASG12D for growth and survival.
Moreover, in multiple KRASG12D-mutant PDX models across various tumor types, LY3962673 exhibited anti-tumor activities ranging from growth inhibition to substantial tumor regression. Combination with other anti-cancer agents further enhanced its efficacy.
Overall, these results highlight LY3962673’s potential as a monotherapy or in combination for treating cancers with KRASG12D mutations, offering a promising oral therapeutic option for diverse cancer types.
GFH375/VS-7375 emerges as a promising orally bioavailable compound, exhibiting potent and selective inhibition of KRASG12D (ON/OFF). Preclinical investigations reveal its efficacy in inducing strong tumor regression as a standalone therapy, offering encouraging prospects for addressing KRASG12D-driven cancers. Moreover, synergistic effects are anticipated when combined with Verastem Oncology’s avutometinib, a novel RAF/MEK clamp, as indicated by preclinical models. These findings underscore the potential of GFH375 in both monotherapy and combination settings, positioning it for further development towards clinical studies. The in vitro potency and selectivity, coupled with robust in vivo efficacy, provide a solid foundation for advancing GFH375 towards IND-enabling stages, offering hope for patients harboring KRASG12D mutations and warranting exploration in clinical trials.
For more information, refer to Delveinsight’s KRAS Inhibitors Market Size, Target Population, Competitive Landscape & Market Forecast – 2034 Report.
Article in PDF
