Home Blog of Signal Transduction Cytoskeletal Signaling Akt Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in KRAS-Mutant Pancreatic and Colorectal Cancer

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in KRAS-Mutant Pancreatic and Colorectal Cancer

Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant KRAS pancreatic and colon cancer. SIGNIFICANCE: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.

 

Comments:

The passage you provided discusses a significant finding related to cancer research. Here's a breakdown of the key points mentioned in the text:

1. **PI3K/AKT Signaling Axis:** Abnormalities in the PI3K/AKT signaling pathway are commonly found in various cancer types, underscoring the importance of these pathways in cancer development and progression.

2. **Challenges in AKT Inhibition:** Therapeutic strategies targeting AKT face challenges such as lack of selectivity, limited efficacy, and adverse effects at higher doses.

3. **Discovery of Borussertib:** Researchers have discovered a new compound called borussertib, which acts as a covalent-allosteric inhibitor of AKT1.

4. **Structural Insights:** Scientists have determined the crystal structure of autoinhibited AKT1 in complex with borussertib. This structure provides crucial information about how borussertib inhibits AKT1, offering insights for further drug design and development.

5. **Biological and Preclinical Evaluation:** Borussertib has undergone extensive testing in various cancer-related models. It has demonstrated strong antiproliferative activity in cancer cell lines that have specific genetic alterations within the PTEN, PI3K, and RAS signaling pathways.

6. **Combination Therapy:** Borussertib has shown promising antitumor activity when used in combination with the MEK inhibitor trametinib. This combination therapy was effective in patient-derived xenograft models of pancreatic and colon cancer with mutant KRAS, suggesting a potential treatment strategy for these cancer types.

7. **Clinical Significance:** The findings indicate that borussertib, as a first-in-class covalent-allosteric AKT inhibitor, holds promise as a therapeutic agent. The success of borussertib in combination with trametinib provides a foundation for further optimization, both in terms of pharmacokinetics (how the body affects the drug) and pharmacodynamics (how the drug affects the body). This research represents a significant step forward in the development of targeted therapies for cancer treatment.

This discovery has significant implications for cancer research and opens avenues for developing more effective and targeted treatments for patients with specific genetic alterations in their cancer cells.

Related Products

Cat.No. Product Name Information
S8839 Borussertib Borussertib is a covalent-allosteric inhibitor of protein kinase Akt with an IC50 of 0.8 nM and a Ki of 2.2 nM for WT Akt.

Related Targets

Akt