D-1553 Iupac Name Kras G12c Inhibitor

The relentless pursuit of effective cancer therapies has led to the discovery and development of numerous targeted agents. Among these, KRAS G12C inhibitors have emerged as a beacon of hope, particularly D-1553, a compound gaining significant attention in the oncology community. Understanding the IUPAC name, mechanism of action, and clinical implications of D-1553 is crucial for healthcare professionals, researchers, and anyone interested in the cutting-edge advancements in cancer treatment. This comprehensive article delves into the intricacies of D-1553, exploring its chemical identity, biological activity, preclinical and clinical development, and future prospects.

Deciphering the Identity of D-1553: IUPAC Name and Chemical Structure

The International Union of Pure and Applied Chemistry (IUPAC) nomenclature provides a standardized method for naming chemical compounds, ensuring clarity and precision in scientific communication. D-1553, a promising KRAS G12C inhibitor, has a complex chemical structure that translates into a correspondingly complex IUPAC name. While the exact IUPAC name may vary slightly depending on the source and specific salt form, it typically reflects the arrangement of atoms and functional groups within the molecule.

Given the proprietary nature of many drug compounds, the full IUPAC name of D-1553 might not be publicly available in complete detail. However, the core structural features and the nature of the molecule as a substituted heterocyclic compound can be inferred from published research and patent literature. The IUPAC name would essentially describe the precise connectivity and stereochemistry of the various rings, chains, and functional groups attached to the central scaffold of the molecule.

The chemical structure of D-1553 is paramount to its function. It consists of a core scaffold, likely a heterocyclic ring system, decorated with various substituents that enhance its binding affinity and selectivity for the KRAS G12C protein. These substituents are carefully chosen to optimize interactions with the unique microenvironment of the G12C mutation site on the KRAS protein. Understanding the structure-activity relationship (SAR) is essential in drug development, as it guides the optimization of the molecule for improved potency, selectivity, and pharmacokinetic properties.

The Significance of KRAS G12C Inhibition: A Deep Dive

The KRAS gene encodes a small GTPase protein that plays a crucial role in cell signaling pathways regulating cell growth, differentiation, and survival. Mutations in KRAS are among the most common oncogenic drivers, occurring in approximately 20% of all human cancers. The G12C mutation, specifically, involves a substitution of glycine at position 12 with cysteine. This seemingly subtle change creates a unique vulnerability that can be exploited by specifically designed inhibitors.

For decades, KRAS was considered an "undruggable" target due to the protein's smooth surface and high affinity for GTP, making it difficult to design small molecules that could effectively bind and inhibit its activity. However, the discovery of covalent inhibitors that specifically target the cysteine residue in KRAS G12C has revolutionized the field. These inhibitors form a strong, irreversible bond with the cysteine, effectively locking the KRAS protein in an inactive state.

The significance of KRAS G12C inhibition lies in its potential to selectively target and kill cancer cells harboring this specific mutation while sparing normal cells. This targeted approach minimizes off-target effects and reduces the toxicity associated with traditional chemotherapy. KRAS G12C inhibitors have shown remarkable efficacy in preclinical models and early clinical trials, leading to their rapid development and approval for certain cancer types.

D-1553: Mechanism of Action and Preclinical Efficacy

D-1553 is a highly selective and potent inhibitor of KRAS G12C. Its mechanism of action involves the formation of a covalent bond with the cysteine residue at position 12 of the KRAS protein. This covalent modification disrupts the protein's ability to bind to GTP and GDP, effectively locking it in an inactive state and preventing downstream signaling.

The inactivation of KRAS G12C by D-1553 leads to a cascade of downstream effects, including:

• Inhibition of cell proliferation: By blocking the KRAS signaling pathway, D-1553 inhibits the uncontrolled growth of cancer cells.
• Induction of apoptosis: D-1553 triggers programmed cell death in KRAS G12C-mutant cancer cells.
• Suppression of tumor angiogenesis: D-1553 inhibits the formation of new blood vessels that supply tumors with nutrients and oxygen.
• Modulation of the tumor microenvironment: D-1553 can alter the composition and activity of cells within the tumor microenvironment, making it more susceptible to immune attack.

Preclinical studies have demonstrated the remarkable efficacy of D-1553 in various cancer cell lines and animal models harboring the KRAS G12C mutation. These studies have shown that D-1553 can significantly reduce tumor size, prolong survival, and prevent metastasis. Furthermore, D-1553 has exhibited favorable pharmacokinetic and pharmacodynamic properties, making it a promising candidate for clinical development.

Clinical Development of D-1553: Trials and Tribulations

The promising preclinical data on D-1553 have spurred its rapid advancement into clinical trials. These trials are designed to evaluate the safety, efficacy, and optimal dosage of D-1553 in patients with KRAS G12C-mutant cancers. Clinical trials typically involve several phases:

• Phase 1 trials: These trials focus on assessing the safety and tolerability of D-1553 in a small group of patients. The primary goal is to determine the maximum tolerated dose (MTD) and identify any dose-limiting toxicities (DLTs).
• Phase 2 trials: These trials evaluate the efficacy of D-1553 in a larger group of patients with a specific type of KRAS G12C-mutant cancer. The primary endpoint is often the objective response rate (ORR), which measures the percentage of patients whose tumors shrink or disappear in response to treatment.
• Phase 3 trials: These trials compare D-1553 to the standard of care in a large, randomized group of patients. The primary endpoint is often overall survival (OS) or progression-free survival (PFS), which measure how long patients live or remain without their cancer progressing.

The clinical development of D-1553 has faced several challenges, including:

• Patient selection: Identifying patients who are most likely to benefit from D-1553 requires accurate and reliable testing for the KRAS G12C mutation.
• Drug resistance: Some patients may develop resistance to D-1553 over time, limiting its long-term efficacy.
• Adverse events: D-1553 can cause side effects, such as nausea, fatigue, and diarrhea, which may require dose adjustments or supportive care.
• Combination strategies: Determining the optimal combination of D-1553 with other cancer therapies, such as chemotherapy or immunotherapy, is an ongoing area of research.

Despite these challenges, the clinical trials of D-1553 have shown promising results in patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) and other solid tumors. These results have led to accelerated regulatory approvals and have established D-1553 as a valuable treatment option for these patients.

D-1553 in Non-Small Cell Lung Cancer (NSCLC)

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all cases. KRAS mutations occur in approximately 25% of NSCLC cases, with the G12C mutation being the most prevalent subtype. D-1553 has shown significant clinical activity in patients with KRAS G12C-mutant NSCLC who have progressed on or after prior systemic therapy.

Clinical trials have demonstrated that D-1553 can induce durable responses and improve survival in these patients. The objective response rate (ORR) with D-1553 monotherapy has been reported to be in the range of 30-40%, with a median duration of response (DoR) of several months. These results are particularly encouraging, as patients with KRAS G12C-mutant NSCLC often have limited treatment options.

D-1553 has also been investigated in combination with other therapies, such as chemotherapy and immunotherapy, in patients with KRAS G12C-mutant NSCLC. These combination strategies aim to enhance the efficacy of D-1553 and overcome potential resistance mechanisms. Early results from these studies have been promising, suggesting that D-1553 may play an even greater role in the treatment of NSCLC in the future.

D-1553 in Other Solid Tumors

While D-1553 has shown the most promise in NSCLC, it is also being evaluated in clinical trials for other solid tumors harboring the KRAS G12C mutation. These tumors include colorectal cancer, pancreatic cancer, and other less common cancer types. The prevalence of KRAS G12C mutations varies across different cancer types, with colorectal cancer being the second most common indication.

Early results from clinical trials of D-1553 in these other solid tumors have been mixed. While some patients have experienced significant responses, others have not responded as well. This variability may be due to differences in the tumor microenvironment, the presence of other genetic mutations, or the specific signaling pathways that are activated in different cancer types.

Ongoing research is focused on identifying biomarkers that can predict which patients with these other solid tumors are most likely to benefit from D-1553. These biomarkers may include specific gene expression profiles, protein levels, or immune cell populations. By identifying these predictive biomarkers, clinicians can personalize treatment decisions and ensure that D-1553 is used in the patients who are most likely to respond.

Overcoming Resistance to D-1553: Future Directions

Despite the initial success of D-1553, many patients eventually develop resistance to the drug. This resistance can occur through various mechanisms, including:

• Acquisition of secondary mutations: Cancer cells can acquire new mutations in KRAS or other genes that bypass the inhibitory effects of D-1553.
• Activation of alternative signaling pathways: Cancer cells can activate other signaling pathways that compensate for the loss of KRAS signaling.
• Changes in the tumor microenvironment: The tumor microenvironment can evolve to protect cancer cells from the effects of D-1553.

Overcoming resistance to D-1553 is a major focus of ongoing research. Several strategies are being investigated, including:

• Developing next-generation KRAS G12C inhibitors: These inhibitors are designed to overcome the resistance mechanisms that have emerged with the first-generation inhibitors.
• Combining D-1553 with other targeted therapies: This approach aims to simultaneously target multiple signaling pathways and prevent the development of resistance.
• Combining D-1553 with immunotherapy: This approach aims to enhance the immune system's ability to recognize and kill cancer cells.
• Developing personalized treatment strategies: This approach involves tailoring treatment decisions to the specific genetic and molecular characteristics of each patient's tumor.

By pursuing these strategies, researchers hope to extend the duration of response to D-1553 and improve the long-term outcomes for patients with KRAS G12C-mutant cancers.

The Future of KRAS G12C Inhibition: Beyond D-1553

D-1553 represents a significant step forward in the treatment of KRAS G12C-mutant cancers. However, it is just the beginning of a new era in targeted cancer therapy. Ongoing research is focused on developing even more effective KRAS G12C inhibitors, as well as exploring new strategies for targeting other KRAS mutations.

The future of KRAS G12C inhibition may involve:

• Developing allosteric inhibitors: These inhibitors bind to a different site on the KRAS protein than the G12C mutation site, potentially overcoming resistance mechanisms.
• Developing PROTACs (proteolysis-targeting chimeras): These molecules induce the degradation of the KRAS protein, leading to a more complete and durable inhibition of its activity.
• Developing KRAS vaccines: These vaccines aim to stimulate the immune system to recognize and kill KRAS-mutant cancer cells.
• Developing KRAS-directed CAR-T cell therapy: This approach involves engineering immune cells to specifically target and kill KRAS-mutant cancer cells.

These innovative approaches hold the promise of further improving the outcomes for patients with KRAS-mutant cancers and potentially curing these diseases.

Conclusion

D-1553, a potent and selective KRAS G12C inhibitor, has emerged as a promising therapeutic agent for patients with KRAS G12C-mutant cancers, particularly non-small cell lung cancer. Its mechanism of action involves the covalent modification of the cysteine residue at position 12 of the KRAS protein, leading to the inhibition of cell proliferation, induction of apoptosis, and suppression of tumor angiogenesis. Clinical trials have demonstrated that D-1553 can induce durable responses and improve survival in patients with KRAS G12C-mutant NSCLC and other solid tumors.

Despite its initial success, resistance to D-1553 remains a major challenge. Ongoing research is focused on developing next-generation KRAS G12C inhibitors, combining D-1553 with other therapies, and developing personalized treatment strategies to overcome resistance and improve long-term outcomes. The future of KRAS G12C inhibition holds great promise, with the development of allosteric inhibitors, PROTACs, KRAS vaccines, and KRAS-directed CAR-T cell therapy. These innovative approaches may ultimately lead to the cure of KRAS-mutant cancers. Understanding the complexities of D-1553, from its IUPAC name to its clinical implications, is essential for advancing the field and improving the lives of patients with these devastating diseases.