Abstract 4380: HBW-016-K, a novel orally available pan-KRAS inhibitor targeting both “ON” and “OFF” states, is potent, selective, efficacious, safe, and high tissue-penetrant
Bibliographic record
Abstract
Purpose: This study aimed to develop a novel, orally available pan-KRAS inhibitor capable of targeting both the “ON” and “OFF” states of KRAS, addressing drug resistance and expanding treatment options for KRAS-mutant cancers. Methods: Through medicinal chemistry efforts, we designed and optimized a pan-KRAS inhibitor that selectively targets various KRAS mutant subtypes while sparing wild-type KRAS, NRAS, and HRAS. The lead compound was further evaluated for its pharmacokinetic (PK) properties and safety profile. Its anti-tumor efficacy was assessed in multiple KRAS mutant mouse models following oral administration. Results: HBW-016-K demonstrated potent inhibition of various KRAS mutant cell lines with excellent selectivity for KRAS wild-type and other RAS isoforms. This compound effectively targets both the “ON” and “OFF” conformations of KRAS G12D. Additionally, HBW-016-K exhibits favorable PK properties and significant tissue penetration, particularly in lung, intestine, and pancreas. In a KRAS G12V mouse xenograft model, HBW-016-K exhibited dose-dependent anti-tumor activity. At the highest dose of 30 mg/kg (BID, PO), tumors shrank by 84.1% compared to baseline, with sustained tumor regression. HBW-016-K also demonstrated potent anti-tumor activity in KRAS G12D and G12C mouse models. Preliminary toxicity studies revealed a favorable safety profile for HBW-016-K, including minimal off-target effects, negative mutagenicity, and excellent tolerability in a 14-day rat toxicity study. Conclusion: HBW-016-K is a promising novel pan-KRAS inhibitor with superior potency, selectivity, and efficacy. Its favorable PK profile and safety profile support its advancement into clinical development. HBW-016-K has the potential to significantly impact the treatment of KRAS-driven cancers, particularly those with limited therapeutic options, such as lung, colorectal, and pancreatic cancer. Citation Format: Ning Lee, Yingfu Li, Guanfeng Liu, Jiang Li, Mao Yang, Zhiguan Song. HBW-016-K, a novel orally available pan-KRAS inhibitor targeting both “ON” and “OFF” states, is potent, selective, efficacious, safe, and high tissue-penetrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4380.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".