No abstract

CDK8 is a member of the CDK family in which belongs to the serine/threonine protein kinase. It binds with cyclin C to regulate the transcription. By modulation of various gene expression programs, CDK8 associated with the mediator complex to sustain proliferation and viability of cancer cells. CDK8 has been identified as an important factor in cancer occurrence and development. It also involves in the regulation of cancer cell stress response to radiotherapy and chemotherapy, assists tumor cell invasion, metastasis and drug resistance. Therefore inhibition of CDK8 is regarded as a promising target for cancer therapy. ABM-3249 was discovered as a potent and selective CDK8 inhibitor with a novel chemical structure. It inhibited CDK8 kinase activity in biochemical assay and cellular binding assay, with IC50 values of 1.4 nM and 19nM respectively. ABM-3249 displayed good kinase selectivity: <50% inhibition on all other CDK family members at 1uM. Consistently, ABM-3249 reduced STAT1-S727 phosphorylation with an IC50 of less than 100nM. ABM-3249 showed good ADME properties with high oral bioavailability (~90%) in rodents. In efficacy studies, ABM-3249 exhibited excellent anti-tumor activities in multiple in vivo models. In an AML MV4-11 xenograft model at 25mpk oral dosing ABM-3249 achieved complete remission in all mice within 17 days and no tumor recurrence within one month after drug withdrawal. ABM-3249 showed good efficacies as a single agent, as well as a synergetic effect with anti-PD1 combination in a murine colon cancer MC38 model. It also showed an efficacy in a murine colon cancer B16F10 metastasis model. In addition, ABM-3249 displayed a good safety margin in a preliminary tox screen in rodents. Citation Format: Chen Chen, Charles Huang, Min Xu, Xiuquan Chen, Xiaobing Lv, Chen Yang, Lanjiao Zhao, YouQin Chen, Jizhi Li, Li Zhao. A potent and selective CDK8 inhibitor ABM-3249 with excellent efficacies in multiple in vivo cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5982.

The Mitogen-Activated Extracellular Signal-Regulated Kinase (MEK) is a critical member of the MAPK signaling pathway family. In cancer cells, the abnormality in MAPK pathway associates with the mutation occurred in the upstream KARS or BRAF. Blockage of the pathway with MEK1/2 inhibitors result in inhibiting cell proliferation and inducing apoptosis. It hence has the potential for clinical benefits for treating cancers with RAS/RAF dysfunctions.ABM-168 is a novel small molecule, allosteric, highly selective MEK inhibitor with high water solubility, cell permeability and brain penetration. We have demonstrated its anti-cancer efficacy in vitro in multiple cancer cell lines, and in vivo in several xenograft, subcutaneous, intracardiac and intracranial, animal models. In-vitro data showed the similar on-target enzyme activity of ABM-168 to marketed MEK inhibitors, as well as high anti-proliferation activities (IC50 <30nM) in multiple cancer cell lines with BRAF or RAS or NF1 mutation like A375, Colo-829, HT-29, MiaPaca-2, LN-229 etc. In vivo pharmacology studies demonstrated that ABM-168 had good potencies of tumor growth inhibitions with oral dose alone or combo with other drugs or compounds in multiple xenograft cancer models: In an A375-luc intracardiac melanoma metastatic model, ABM-168 at 2 mg/kg PO BID demonstrated an antitumor activity comparable to ABM-1310 (A highly BBB-permeable BRAF inhibitor developed by ABM Therapeutics) at different dose levels and frequencies. On Day 28, the BLI% decreased 95.5%, 93.2%, 99.44% and 99.7% for ABM-168 (2 mg/kg), ABM-1310 at 1 mg/kg PO QD, 5 mg/kg PO QD and 2.5 mg/kg PO BID, respectively. In a LN229 glioblastoma orthotopic model in BALB/c nude mice, ABM-168 at 5-10 mg/kg PO QD showed a significant activity, the BLI (%) decreased in the brain 68 % on Day 49. These results indicate that the BBB-permeable ABM-168 may be efficacious as a single agent or combo with ABM-1310 to treat BRAF-mutant, advanced cancers with or without brain metastases or primary CNS tumors with an abnormal up-regulated MAPK signal. Non-clinical pharmacokinetics studies also showed that ABM-168 had a favorable ADME profile both in vitro and in vivo, and good brain penetration in animals. Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs were all completed. Based on these supportive preclinical study results, the IND of ABM-168 was submitted in 2022 Q3 to investigate its safety in human, which will be followed by further clinic development as a single agent, or in combination with other molecules to treat advanced cancers resulted from the abnormal MAPK signal pathway, particularly with brain tumors. Citation Format: Chen Chen, Charles Huang, Min Xu, YouQin Chen, Lanjiao Zhao, Yang Chen, Yong Hu. Preclinical development of ABM-168, a novel MEK Inhibitor to treat cancer with brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 475.

ABM-1310 is a novel small-molecule BRAF inhibitor designed to treat primary CNS tumors or advanced cancer patients with BRAFv600 mutation, with or without brain metastasis. Currently, a Phase I clinical trial of ABM-1310 is actively recruiting patients at multiple clinical centers in US.BRAF mutation takes place in about 8% of all tumors, among which around 90% is V600E amino acid mutation. BRAFv600 mutation causes BRAF’s continuous activation, and results in cancerous cells eventually. Melanoma is the most common cancer type with BRAFv600 mutation, and ~50% of melanoma will develop brain metastasis. Similar situation also occurs in other cancer types like papillary carcinoma of thyroid gland, low-grade serous ovarian carcinoma, colon cancer, and lung cancer with lower rate. A few of primary CNS solid tumors also have significant BRAFv600 mutation rate. Currently, FDA has approved three combination therapy of BRAF inhibitor (i.e., dabrafenib/Tafinlar®, vemurafenib/Zelboraf®, and encorafenib/Braftovi®) to treat patients with unresectable or metastatic melanoma, with metastatic NSCLC, with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation. These combination therapies of BRAF and MEK inhibitors demonstrated clinical benefit, but they all shown poor efficacy on intracranial tumor lesions, which may be due to the limited BBB-penetration of these BRAF/MEK inhibitors. Thus, to treat intracranial tumors with BRAFv600 mutation is still a big unmet medical need currently. Here, we shown preclinical results that ABM-1310 has significantly improved BBB-penetration compared with approved BRAF inhibitors: in mice, B/P ratio and Kp,uu values were 0.2 and 0.2 for Vemurafenib, 0.025 and 0.021 for Dabrafenib, 0.006 and 0.03 for Encorafenib, 0.27 and 1.0 for ABM-1310. Also, in the A375-luc intracranial model, ABM-1310 alone or combo with ABM proprietary, BBB-penetrable MEK inhibitor ABM-168, demonstrated significant improved antitumor activity and animal medial survival time (MST) compared with combination regimens of other BRAF/MEK inhibitors (vemurafenib + cobimetinib, dabrafenib + trametinib, or encorafenib + binimetinib). Either ABM-1310 as a single agent or the combination of ABM-1310 and ABM-168 showed a BLI decrease (%) > 99% on Day 26 and MST of > 69 days, while MST for vehicle was 27 days, and MST for the combo of Dabrafenib and Trametinib was 33 days. In a primary GBM model (DBTGR-05MG, a BRAFv600 mutant GBM cell line), the similar result was demonstrated. Citation Format: Chen Chen, Charles Huang, Min Xu, YouQin Chen, Lanjiao Zhao, Xiaobing Lv, Chen Yang, Yong Hu. ABM-1310 has significant improved BBB-penetration and intracranial tumor growth inhibition compared to FDA approved BRAF inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 476.