Abstract 5802: An orally available small molecule JMBI-001 elicits MYC-synthetic lethality and anti-tumor immunity by disabling MKLP2-mediated cellular processes
Bibliographic record
Abstract
Abstract The MYC oncogene, a pivotal regulator of various cellular processes, is deregulated in approximately 70 % of human malignancies. Mitotic Kinesin-like Protein 2 (MKLP2) plays a versatile role in both interphase and mitosis and has emerged as a significant prognostic indicator and therapeutic target in cancer. The undruggability of MYC and the scarcity of MKLP2 inhibitors, however, have impeded clinical translation. Our development of JMBI-001, a potent and orally bioavailable small-molecule compound, overcomes these barriers. JMBI-001 elicits loss of function phenotypes in MKLP2 and a synthetic lethal interaction with MYC overexpression. Extensive kinome and safety profiling have revealed no significant off-target effects, and the compound is well-tolerated in long-term animal studies. In preclinical models, JMBI-001 has demonstrated an average tumor growth inhibition rate of 75 % across more than 20 MYC-overexpressing tumor models, including those in the stomach, lung, colon, liver, breast, kidney, skin, and hematopoietic system. Its anti-tumor activity positively correlates with high MYC abundance, aligning with the selective eradication of cells with abundant MYC both in vitro and in vivo. Notably, JMBI-001 also robustly stimulates systemic anti-tumor immunity, enhancing NK and CD3+ T cell infiltration in tumors of syngeneic cancer models. Moreover, additive or synergistic effects have been observed when combined with anti-PD1 therapy even in tumors refractory to the immune checkpoint blockade (ICB) therapy. The dual therapeutic actions of JMBI-001 stem from its disruption of MKLP2 functionalities, leading to anomalies, such as Golgi fragmentation in interphase and multipolarity in pro-metaphase. These disruptions lead to two key outcomes: apoptosis and immunogenic cell death, marked by secreted ATP, released high mobility group protein B1 (HMGB1), and surface-exposed calreticulin. These abnormalities, primed and amplified by deregulated MYC, are not observed in non-transformed cells, suggesting their potential as pharmacodynamic markers for monitoring JMBI-001's activity in vivo. In conclusion, JMBI-001 represents a novel class of anticancer agents that simultaneously triggers MYC synthetic lethality and anticancer immunity by targeting MKLP2-mediated cellular processes. Its unique mechanisms of action, exceptional bioavailability, potency at low nanomolar concentrations, wide-spectrum efficacy, and favorable safety profile establish JMBI-001 as a promising clinical study-ready drug candidate for treating MYC-driven cancers. Citation Format: Ting Zhang, Qiong Shi, Julia Kalashova, Xumei Liu, Xiaohu Zhou, Chenglu Yang, Yan Long, Hongmei Li, Jinhua Li, Gang Lv, Duo Yu, Xuejiao Jiang, Shenqiu Zhang, Jing Zhang, Hong Liu, Dun Yang. An orally available small molecule JMBI-001 elicits MYC-synthetic lethality and anti-tumor immunity by disabling MKLP2-mediated cellular processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5802.
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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) | 0.004 | 0.001 |
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".