Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance

Jiang, Zhiyan; Li, Yan; Zhou, Xin; Wen, Jie; Zheng, Pengwu; Zhu, Wufu

doi:10.1016/j.bmc.2024.117627

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…The warhead dependence is modest both within the a and b series showing that warhead variation does not have a significant effect on the noncovalent binding probably because their contribution is less important than that of the scaffold. Although KRAS G12C inhibitors were developed along the electrophile-first approach whereby a covalent ligand was searched from the outset, 12 scaffolds developed 19 to interact with the protein and present the warhead to Cys12 are primarily responsible to the ligand-protein recognition. Nevertheless, it is worth noting that the noncovalent binding affinity of KRAS G12C inhibitors is the modest, being in the 10 μM or higher range corresponding to approximately −6 kcal/mol or less negative binding free energy.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The majority of reported KRAS G12C inhibitors, including those in clinical trials contain acrylamide warhead. , In order to screen further potential warheads targeting Cys12, several electrophiles were tested against KRAS G12C by McGregor and co-workers. Five warheads were found to have high affinity toward the mutant KRAS G12C with no or slight binding to the wild-type protein, in particular, the acrylamide, two aziridine isomers, chloroacetamide, and acyl imidazole …”

Section: Introductionmentioning

confidence: 99%

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Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas^G12C

Péczka,

Ranđelović,

Orgován

et al. 2024

ACS Chem. Biol.

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Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions. Noncovalent and covalent binding steps can be characterized by an equilibrium dissociation constant (K I ) and a reaction rate constant (k inact ), respectively, and they are affected by both the warhead and the scaffold of the ligand. The relative contribution of these two steps was investigated on a prototypic drug target KRAS G12C , an oncogenic mutant of KRAS. We used a synthetically more accessible nonchiral core derived from ARS-1620 that was equipped with four different warheads and a previously described KRAS-specific basic side chain. Combining these structural changes, we have synthesized novel covalent KRAS G12C inhibitors and tested their binding and biological effect on KRAS G12C by various biophysical and biochemical assays. These data allowed us to dissect the effect of scaffold and warhead on the noncovalent and covalent binding event. Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRAS G12C inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas^G12C

Péczka,

Ranđelović,

Orgován

et al. 2024

ACS Chem. Biol.

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“…Based on these observations, we designed the synthesis of new set of quinoline-acrylamide hybrids 5 and 6a–i to be checked for their cytotoxic potential and EGFR kinase inhibition. The target derivatives will incorporate both quinoline-4-carbohydrazide structure as apoptosis inducer 29 connected to 3-arylacrylamide moiety, which was reported to efficiently inhibit kinase receptor 30,31 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization and biological research of novel 2-(quinoline-4-carbonyl)hydrazide-acrylamide hybrids as potential anticancer agents on MCF-7 breast carcinoma cells by targeting EGFR-TK

Abd El-Lateef,

Bafail,

Alhalees

et al. 2024

RSC Adv.

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The Pivotal Role of Preclinical Animal Models in Anti-Cancer Drug Discovery and Personalized Cancer Therapy Strategies

Guo,

Xu,

Zhang

et al. 2024

Pharmaceuticals

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The establishment and utilization of preclinical animal models constitute a pivotal aspect across all facets of cancer research, indispensably contributing to the comprehension of disease initiation and progression mechanisms, as well as facilitating the development of innovative anti-cancer therapeutic approaches. These models have emerged as crucial bridges between basic and clinical research, offering multifaceted support to clinical investigations. This study initially focuses on the importance and benefits of establishing preclinical animal models, discussing the different types of preclinical animal models and recent advancements in cancer research. It then delves into cancer treatment, studying the characteristics of different stages of tumor development and the development of anti-cancer drugs. By integrating tumor hallmarks and preclinical research, we elaborate on the path of anti-cancer drug development and provide guidance on personalized cancer therapy strategies, including synthetic lethality approaches and novel drugs widely adopted in the field. Ultimately, we summarize a strategic framework for selecting preclinical safety experiments, tailored to experimental modalities and preclinical animal species, and present an outlook on the prospects and challenges associated with preclinical animal models. These models undoubtedly offer new avenues for cancer research, encompassing drug development and personalized anti-cancer protocols. Nevertheless, the road ahead continues to be lengthy and fraught with obstacles. Hence, we encourage researchers to persist in harnessing advanced technologies to refine preclinical animal models, thereby empowering these emerging paradigms to positively impact cancer patient outcomes.

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Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance

Cited by 3 publications

References 44 publications

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas^G12C

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas^G12C

Synthesis, characterization and biological research of novel 2-(quinoline-4-carbonyl)hydrazide-acrylamide hybrids as potential anticancer agents on MCF-7 breast carcinoma cells by targeting EGFR-TK

The Pivotal Role of Preclinical Animal Models in Anti-Cancer Drug Discovery and Personalized Cancer Therapy Strategies

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Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance

Cited by 3 publications

References 44 publications

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRasG12C

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRasG12C

Synthesis, characterization and biological research of novel 2-(quinoline-4-carbonyl)hydrazide-acrylamide hybrids as potential anticancer agents on MCF-7 breast carcinoma cells by targeting EGFR-TK

The Pivotal Role of Preclinical Animal Models in Anti-Cancer Drug Discovery and Personalized Cancer Therapy Strategies

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Product

Resources

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Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas^G12C

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas^G12C