BBO-11818: An Orally Bioavailable Pan-KRAS Inhibitor for KRAS-related Cancer Research

KRAS is a major oncogenic driver in multiple cancers, with clinically relevant mutations including KRASG12D, KRASG12V, and KRASG12C. Although KRASG12C inhibitors have demonstrated clinical benefit, effective therapies for other KRAS mutants remain limited. Moreover, many pan-KRAS inhibitors preferentially target the inactive GDP-bound KRAS (OFF) state, potentially limiting their activity against strongly activated KRAS.

BBO-11818 is a potent, selective, orally bioavailable, and noncovalent pan-KRAS inhibitor capable of targeting multiple KRAS mutants in both their active (ON) and inactive (OFF) states.

Note: MCE provides BBO-11818(HY-181420A) for research use only. We do not sell to patients.

BBO-11818 is a potent and selective dual-state pan-KRAS inhibitor

BBO-11818 binds KRASG12D, KRASG12V, and KRASWT in both GDP- and GTP-bound states, with >500-fold selectivity over NRAS and HRAS. BBO-11818 disrupts KRAS-RAF1 interaction, inhibiting RAF1-RBD binding to KRASG12D, KRASG12V, KRASG12C, KRASG12R, and KRASWT. The corresponding IC50 values are 28, 61, 47, 51, and 120 nM, respectively.

Crystal structures show BBO-11818 binding between Switch-II and Helix 3 of KRASG12D in both nucleotide states. This binding induces an inactive Switch-I conformation, thereby preventing KRAS interaction with downstream effectors.

BBO-11818 further suppresses KRAS signaling by shifting GTP-bound KRAS toward an inactive conformation and inhibiting SOS-mediated nucleotide exchange. It inhibits nucleotide exchange of both KRASWT and oncogenic KRAS mutants. Consistent with ON-state activity, BBO-11818 maintains strong MAPK inhibition after EGF stimulation. It also suppresses pERK and pAKT signaling in KRASG12D and constitutively active KRASG12D/A59G models.

BBO-11818 demonstrates potent cellular and in vivo antitumor activity

Figure 1. BBO-11818 demonstrates dose- and time-dependent inhibition of pERK.

BBO-11818 strongly inhibits MAPK signaling and proliferation across KRASG12D, KRASG12V, and KRASG12C cancer models. In 88 cancer cell lines, mean EC50 values were 2.21, 31.2, and 2.26 nM for KRASG12D, KRASG12V, and KRASG12C, respectively. BBO-11818 showed limited activity in non-KRAS-driven models.

Oral BBO-11818 produced sustained tumor pERK inhibition in a KRASG12D PDAC xenograft model. Single doses of 30 and 100 mg/kg reduced pERK by approximately 45% and 85% at 6 hours, respectively. Repeated dosing strongly inhibited tumor growth and induced regression across multiple KRAS-mutant models. BBO-11818 achieved 87% tumor growth inhibition and 57% mean tumor regression in KRASG12D PDAC. It induced 69% mean tumor regression in KRASG12D colorectal cancer and 99% tumor growth inhibition in KRASG12V NSCLC.

BBO-11818 shows strong combination potential and has entered Phase I development

BBO-11818 demonstrated promising combination activity with immune checkpoint and targeted therapies. In a KRASG12D colorectal cancer syngeneic model, combination with anti–PD-1 increased median survival to 50 days, compared with 19–25 days for vehicle or either monotherapy. Notably, 44% of mice achieved complete tumor regression and remained tumor-free following tumor rechallenge, suggesting durable antitumor immunity.

Combination with the RASα breaker BBO-10203 also enhanced efficacy, producing 40% mean tumor regression in a KRASG12V PDAC model and 63% mean tumor regression in a KRASG12D NSCLC PDX model. BBO-11818 also showed robust combination activity with cetuximab, supporting EGFR blockade as a potential strategy to suppress bypass signaling and overcome adaptive resistance to KRAS inhibition.

BBO-11818 has entered a Phase I clinical trial in patients with colorectal cancer, PDAC, or NSCLC harboring KRASG12A, KRASG12C, KRASG12D, KRASG12S, or KRASG12V mutations, or KRAS amplification (NCT06917079). Its ability to target both KRAS ON and OFF states, together with broad mutant coverage and oral bioavailability, supports its potential as both a monotherapy and combination therapy.

In summary

BBO-11818 is a potent, selective, orally bioavailable, and noncovalent pan-KRAS inhibitor targeting multiple clinically relevant KRAS mutants in both ON and OFF states. It disrupts KRAS-RAF1 signaling, inhibits SOS-mediated nucleotide exchange, and produces robust antitumor activity in KRAS-driven cancer models.

Its enhanced efficacy in combination with anti–PD-1, anti-EGFR, and RASα pathway-targeted therapies further highlights its potential for overcoming adaptive resistance and improving therapeutic responses in KRAS-driven cancers.

References

[1]. Stahlhut C, et al. Cancer Discov. 2026 Apr 1;16(4):740–759. [Content Brief]