- |||||||||| RGT-018 / Regor
Journal: Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers. (Pubmed Central) - Aug 1, 2024
FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation...Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors...Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.
- |||||||||| Identifying Resistant Mechanisms To Direct KRAS-Inhibitors (Grace Murray Hopper Auditorium, Yale West Campus Conference Center) - Jun 23, 2024 - Abstract #LUNGSPORE2024LUNG_SPORE_28;
The identification of selective inhibitors of other oncogenic KRAS alleles, such as the noncovalent KRAS-G12D inhibitor, MRTX1133, and a pan-KRAS-inhibitor drug, BI3706674 is also a promising next step in the treatment of KRAS-dependent malignancies...We are currently performing in vitro and In vivo studies to understand the therapeutic efficacy of a TEAD inhibitor (VT107) in combination with KRASi (MRTX849 or MRTX1133) to either reverse or prevent resistance to the direct KRAS inhibitors. Successful completion of this research will help address the urgent need to understand ways to overcome resistance to KRAS inhibitors and increase their clinical efficacy.
- |||||||||| Journal, Combination therapy: Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer. (Pubmed Central) - Jun 19, 2024
In the current work presented here, pancreatic cancer cell lines with oncogenic KRAS G12C, G12D, or wild-type KRAS were treated with specific KRAS or SOS1/2 inhibitors, and therapeutic synergisms with concomitant MEK inhibition and irradiation were systematically evaluated by means of cell viability, 2D-clonogenic, 3D-anchorage independent soft agar, and bioluminescent ATP assays. Underlying pathophysiological mechanisms were examined by using Western blot analyses, apoptosis assay, and RAS activation assay.
- |||||||||| MRTX1133 / BMS
Preclinical, Review, Journal: Structural perspectives on recent breakthrough efforts toward direct drugging of RAS and acquired resistance. (Pubmed Central) - Jun 6, 2024
Of interest, the non-covalent KRASG12D targeting inhibitor MRTX-1133 has shown promising results in humanized pancreatic cancer mouse models and is seemingly making its way from bench to bedside...Finally, the next generation of KRAS mutant-specific and pan-RAS tri-complex inhibitors have revolutionized RAS drug discovery. This review will give a structural biology perspective on the current generation of KRAS inhibitors through the lens of emerging secondary mutations and acquired resistance.
- |||||||||| Enweida (envafolimab) / 3DMed, Tracon Pharma, Ascletis
Journal, PD(L)-1 Biomarker, IO biomarker: Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins. (Pubmed Central) - May 31, 2024
Our study demonstrates that EPOY, when incorporated into a nanobody (KN035), can cross-link with different side chains (mutations) at the same position of PD-L1 protein...This covalent KRAS binder holds the potential to achieve pan-covalent targeting of KRAS based on the structural similarity among all oncogenic KRAS mutants while avoiding off-target binding to NRAS/HRAS through a covalent interaction with KRAS-specific residues (H95 and E107). We envision that covalently targeting to H95 will be a promising strategy for the development of covalent pan-KRAS inhibitors in the future.
- |||||||||| Review, Journal: KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance. (Pubmed Central) - Apr 26, 2024
Further, non-mutational forms of resistance can take the form of epigenetic marks, transcriptional reprogramming, or alterations within the tumor microenvironment. As the possible strategies to inhibit KRAS expand, understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal: From bench to bedside: current development and emerging trend of KRAS-targeted therapy. (Pubmed Central) - Mar 18, 2024
In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRAS mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.
- |||||||||| Krazati (adagrasib) / BMS, MRTX1133 / BMS, Lumakras (sotorasib) / Amgen
Identifying resistant mechanisms to direct KRAS inhibitors in NSCLC (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4026;
Recent breakthroughs, however, have resulted in the development of covalent inhibitors capable of selectively targeting the KRAS G12C mutation, like Sotorasib (AMG510) and Adagrasib (MRTX849) which are approved by the FDA due to their encouraging effects in clinical trials...Among the several proteins whose expressions were altered in the KRAS-inhibitor-resistant cells, we identified the YAP/TEAD1 pathway that was commonly upregulated in the cells resistant to MRTX849 (G12Ci) or MRTX1133 (G12Di)...We are also trying to identify alterations in the tumor immune microenvironment upon combination therapy targeting KRAS and TEAD. Successful completion of this research will help address the urgent need to understand ways to overcome resistance to KRAS inhibitors and increase their clinical efficacy.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal: Multiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions. (Pubmed Central) - Feb 19, 2024
We systematically summarize recent advances in the discovery and optimization processes of direct KRAS inhibitors (including KRAS, KRAS, KRAS and KRAS inhibitors), indirect KRAS inhibitors (SOS1 and SHP2 inhibitors), pan-KRAS inhibitors, as well as proteolysis-targetingchimeras degrades and molecular chaperone modulators from the perspective of medicinal chemistry. We also discuss the current challenges and opportunities of KRAS inhibition and hope to shed light on future KRAS drug discovery.
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