Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1168150 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30865828.fastq.gz | Fastqsanger.gz | |||
| SRR30865828_1.fastq.gz | Fastqsanger.gz | |||
| SRR30865828_2.fastq.gz | Fastqsanger.gz | |||
| SRR30865829.fastq.gz | Fastqsanger.gz | |||
| SRR30865829_1.fastq.gz | Fastqsanger.gz |
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Project description:Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form of the protein. This suboptimal mechanism provides no direct target coverage against KRASG12C(ON). Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor activated states where current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of downstream signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C (OFF)-only inhibitors.
2024-10-02 | GSE278656 | GEO
Project description:Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor-activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455.
| S-EPMC11873722 | biostudies-literature
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental Lu65 cells to those with acquired resistance to RM-4998. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055080 | Pride
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental LUN156 patient-derived xenograft tumors to those with acquired resistance to the KRAS G12C inhibitors, Adagrasib (AR) and RM-4998 (RR). Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055133 | Pride
Project description:Inhibitors targeting KRASG12C, a mutant form of the guanosine triphosphatase (GTPase) KRAS, are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by the mutant protein. These molecules react with the mutant cysteine residue by binding covalently to the switch-II pocket (S-IIP) that is present only in the inactive guanosine diphosphate (GDP)-bound state of KRASG12C, sparing the wild-type protein. We used a genome-scale CRISPR interference (CRISPRi) functional genomics platform to systematically identify genetic interactions with the KRASG12C inhibitor in cellular models of KRASG12C mutant lung and pancreatic cancer. Our data revealed genes that were selectively essential in this oncogenic driver-limited cell state, meaning their loss enhanced cellular susceptibility to direct KRASG12C inhibition. We termed such genes “collateral dependencies” (CDs), and identified two classes of combination therapies targeting these CDs that increased KRASG12C target engagement or blocked residual survival pathways in cells and in vivo. From our findings, we also propose a new framework for assessing genetic dependencies with driver oncogenes.
2019-05-03 | GSE130616 | GEO
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental H358 cells to those with acquired resistance to the KRAS G12C inhibitor, AMG510. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055244 | Pride
Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental Lu65 cells to those with acquired resistance to the KRAS G12C inhibitor, Sotorasib. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.
2025-10-08 | PXD055167 | Pride
Project description:KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, one particular form of mutant KRAS, namely KRASG12C, can be targeted by small molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Although our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/ KRASG12C dimerization, and degraded GFP-KRASG12C in GFP reporter cells in a CRBN-dependent manner, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively polyubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and propose several possible solutions which may lead to efficient degradation of endogenous KRASG12C.
2020-01-09 | PXD014646 | Pride
Project description:KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, one particular form of mutant KRAS, namely KRASG12C, can be targeted by small molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Although our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/ KRASG12C dimerization, and degraded GFP-KRASG12C in GFP reporter cells in a CRBN-dependent manner, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively polyubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and propose several possible solutions which may lead to efficient degradation of endogenous KRASG12C.
2020-01-09 | PXD014549 | Pride
Project description:KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, one particular form of mutant KRAS, namely KRASG12C, can be targeted by small molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Although our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/ KRASG12C dimerization, and degraded GFP-KRASG12C in GFP reporter cells in a CRBN-dependent manner, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively polyubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and propose several possible solutions which may lead to efficient degradation of endogenous KRASG12C.
2020-01-09 | PXD014643 | Pride