CDK4/6

In the plasma of healthy persons, the metabolite M18 hydrochloride of abelacilb has a T1/2 of 43.1 hours [3]. The primary mode of action of CDK4/6 inhibitors is to cause cell cycle arrest by blocking the phosphorylation of the retinoblastoma (RB) protein. Other modifications to cancer cell biology are made by CDK4/6 inhibitors [4].

CDK4/6 inhibitors enhanced T cell survival and immunological memory in mice given tumor-specific CD8+ T cells [5].

[1]. Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study. Clin Cancer Res (2018) 24 (22): 5543–5551.

[2]. Degradation of cyclin-dependent kinase 4/6 (cdk4/6) by conjugation of cdk4/6 inhibitors with e3 ligase ligand and methods of use. WO2017185031A1.

[3]. Abstract CT153: Pharmacokinetic drug interactions between abemaciclib and CYP3A inducers and inhibitors. Cancer Res. 2016-7-15; 76 (14_Supplement): CT153.

[4]. CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. Trends Cell Biol. 2018 Nov;28(11):911-925.

[5]. Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation. Cancer Discov. 2021 Oct;11(10):2564-2581.

Objective: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has shown activity in preclinical studies of non-small cell lung cancer (NSCLC). A multicenter, non-randomized, open-label phase Ib study was conducted to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies in patients with metastatic NSCLC. Patients and Methods: A dose-escalation phase was initially performed to determine the MTD of twice-daily oral abemaciclib (150 mg, 200 mg) in combination with pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each combination. Pemetrexed and gemcitabine were administered according to their manufacturer's instructions. The abemaciclib plus ramucirumab study investigated both dosing regimens. Results: A total of 86 patients were enrolled across the three study portions; all patients received at least one dose of combination therapy. The most common adverse events in each treatment group were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. This trial did not determine the maximum tolerated dose (MTD) of abeciclib in combination with pemetrexed or gemcitabine, but it did determine the maximum tolerated dose of abeciclib in combination with ramucirumab (8 mg/kg) on days 1 and 8. Plasma analysis showed that abeciclib did not affect the pharmacokinetics of the combination therapy, nor did the combination therapy affect abeciclib exposure. The disease control rate was 57% in the abeciclib plus pemetrexed group, 25% in the abeciclib plus gemcitabine group, and 54% in the abeciclib plus ramucirumab group. The median progression-free survival was 5.55 months, 1.58 months, and 4.83 months, respectively. Conclusion: Abeciclib in combination with pemetrexed, gemcitabine, or ramucirumab, administered twice daily, is safe and well-tolerated. Abeciclib exposure was consistent with results observed in monotherapy studies. [1]

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Abecil is a selective and potent small-molecule cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitor currently under investigation for the treatment of refractory hormone receptor-positive (HR+) advanced or metastatic breast cancer. In vitro studies have shown that CYP3A is responsible for more than 99% of the CYP-mediated microsomal metabolism of abecil and its active metabolites. Three clinical studies evaluated the in vivo distribution, metabolism, and drug interaction potential of abecil in the presence of the potent CYP3A inducer rifampin or the potent CYP3A inhibitor clarithromycin. In healthy subjects (N = 6), the in vivo distribution and metabolism of abecil were determined following a single oral dose of 150 mg [14C]-abecil. In the rifampicin interaction study, healthy subjects (N = 24) received two single oral doses of 200 mg abexicillin: the first dose was administered alone on day 1 of phase 1, and the second dose was administered in combination with 600 mg rifampicin on day 7 of phase 2, prior to a 6-day once-daily (QD) rifampicin regimen; rifampicin was continued once daily for 7 days after abexicillin administration. In the clarithromycin interaction study, patients with advanced cancer (N = 26) received two single oral doses of 50 mg abexicillin: the first dose was administered alone, and the second dose was administered concurrently with clarithromycin (500 mg twice daily) on day 5 of phase 2, followed by 7 days of continued clarithromycin administration. Abexicillin is extensively metabolized, with less than 10% of the original drug recovered in feces. The original drug and three active metabolites were detected in plasma: LSN2839567 [M2], LSN3106729 [M18], and LSN3106726 [M20]. In healthy subjects, the mean half-lives of abexilide, M2, M18, and M20 were 29.0, 104.0, 55.9, and 43.1 hours, respectively. Compared with abexilide alone, combination therapy with rifampin reduced the AUC(0-?) and Cmax of abexilide by 95% and 92%, respectively, and reduced the AUC(0-?) and Cmax of the total active substance (abecililide + M2 + M18 + M20) by 77% and 45%, respectively. Compared with abexilide alone, combination therapy with clarithromycin increased the AUC(0-?) and Cmax of abexilide by 237% and 30%, respectively; increased the AUC(0-?) of the total active substance by 119%, and reduced the Cmax by 7%. The mean half-life (t1/2) of abexilide increased from 28.8 hours to 63.6 hours. Based on vital signs, clinical laboratory assessments and electrocardiogram data, no clinically significant safety issues were observed after a single dose of abexilide in healthy subjects or patients with advanced cancer. Human absorption, distribution, metabolism and excretion studies have shown that abexilide is primarily eliminated through hepatic metabolism. Clinical drug interaction studies with potent CYP3A inducers and inhibitors have confirmed the major role of CYP3A in abexilide metabolism. Because the presence of potent CYP3A inducers and inhibitors can lead to significant changes in the exposure of abexilide and its active metabolites, concomitant use with these drugs should be avoided, or the dose of abexilide may need to be adjusted. [3] Pharmacological inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have become a treatment option for clinicians in recent years and have shown good efficacy in patients with breast cancer and other cancers. Although the main mechanism of action of CDK4/6 inhibitors is to inhibit the phosphorylation of retinoblastoma (RB) proteins, thereby inducing cell cycle arrest, they also alter cancer cell biology in other ways that can also be used for treatment. These mechanisms include modulating mitogenic kinase signaling pathways, inducing senescence-like phenotypes, and enhancing the immunogenicity of cancer cells. This article describes some little-known effects of CDK4/6 inhibitors on cancer cells and proposes some ways to leverage these effects to enhance their efficacy in cancer patients. [4] CDK4/6 inhibitors have been approved for the treatment of breast cancer and are currently undergoing clinical trials for other malignancies. We investigated the effects of CDK4/6 inhibitors on T cells during the early activation phase of CD8+ T cells in mice and humans. Mice treated with tumor-specific CD8+ T cells and CDK4/6 inhibitors showed enhanced T cell persistence and immune memory. CDK4/6 inhibitors upregulated the expression of MXD4, the negative regulator of MYC, in mouse and human CD8+ T cells. Silencing the Mxd4 or Myc gene in mouse CD8+ T cells suggests the importance of this pathway for memory formation. We evaluated newly activated CD8+ T cells in breast cancer patients before and after treatment with palbociclib or abexicillin using single-cell transcriptome analysis and T cell receptor clonal tracing. In humans, CDK4/6 inhibitor treatment increases the frequency of CD8+ memory precursor cells and downregulates the expression of their MYC target genes, suggesting that CDK4/6 inhibitors may enhance long-term protective immunity in cancer patients. Significance: In mice and breast cancer patients, CDK4/6 inhibitors can convert newly activated CD8+ T cells to a memory phenotype. CDK4/6 inhibitors may have broad application value in areas other than breast cancer, especially in neoadjuvant therapy, where they can enhance the activation of CD8+ T cells against tumor antigens before checkpoint blockade therapy. This article is highlighted in this issue's special feature, page 2355. [5]

C25H29CLF2N8O

531.000570058823

530.212

2704316-82-3

Abemaciclib metabolite M18-d8;Abemaciclib metabolite M18;2704316-81-2

145925653

Off-white to light yellow solid powder

4

10

7

37

701

0

CC(C)N1C2=C(C(=CC(=C2)C3=NC(=NC=C3F)NC4=NC=C(C=C4)CN5CCNCC5)F)N=C1CO.Cl

WGFYSOPSZMTSSV-UHFFFAOYSA-N

InChI=1S/C25H28F2N8O.ClH/c1-15(2)35-20-10-17(9-18(26)24(20)32-22(35)14-36)23-19(27)12-30-25(33-23)31-21-4-3-16(11-29-21)13-34-7-5-28-6-8-34;/h3-4,9-12,15,28,36H,5-8,13-14H2,1-2H3,(H,29,30,31,33);1H

[4-fluoro-6-[5-fluoro-2-[[5-(piperazin-1-ylmethyl)pyridin-2-yl]amino]pyrimidin-4-yl]-1-propan-2-ylbenzimidazol-2-yl]methanol;hydrochloride

Abemaciclib metabolite M18 hydrochloride; 2704316-82-3; Abemaciclib metabolite M18 (hydrochloride); LSN3106729 (hydrochloride); EX-A8463; CDK ligand for PROTAC hydrochloride;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 125 mg/mL (235.40 mM)
H2O : 100 mg/mL (188.32 mM)

Solubility in Formulation 1: 50 mg/mL (94.16 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)