A review of trilaciclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, for the management of metastatic small-cell lung cancer

MEDICINAL CHEMISTRY RESEARCH Medicinal Chemistry Research https://doi.org/10.1007/s00044-024-03288-y REVIEW ARTICLE A review of trilaciclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, for the management of metastatic small-cell lung cancer Twinkle I. Patel1 Jay N. Joshi2 Alexander J. Valvezan2 Matthew J. Moschitto ● ● ● 1 1234567890();,: 1234567890();,: Received: 7 June 2024 / Accepted: 16 July 2024 © The Author(s) 2024 Abstract Cyclin-dependent kinases (CDKs) play a major role in regulating transitions within the cell cycle. Given the roles of CDK4/6 in promoting oncogenesis, selective inhibition of CDK4/6 has emerged as a novel approach for the treatment of breast cancer and various other tumors. While first and second generation CDK4/6 inhibitors were instrumental in targeting cell cycle pathways, they had numerous drawbacks such as limited selectivity and off-target effects. For that reason, a third generation of inhibitors was introduced and provided improved selectivity towards CDK4/6 leading to fewer side effects. To date, four compounds have been approved by the FDA as selective inhibitors of CDK4/6: palbociclib, ribociclib, abemaciclib, and trilaciclib. In this mini review, we summarize the biological, clinical, and chemical aspects of trilaciclib, a first-in-class CDK4/6 inhibitor notable for its dual role in cell cycle regulation and myelopreservation. Trilaciclib was granted FDA approval on February 2021, to improve the outcome of patients with metastatic-stage small cell lung cancer (SCLC) by protecting bone marrow suppression during chemotherapy. Keywords SCLC CDK4/6 Inhibitors Trilaciclib Synthetic Pathway Clinical use ● ● ● Introduction Small-cell lung cancer (SCLC) is an extremely aggressive type of neuroendocrine lung tumor, characterized by genomic instability, rapid proliferation rates, and strong propensity for * Matthew J. Moschitto 1 Department of Medicinal Chemistry, Rutgers, the State University of New Jersey, Piscataway, NJ, USA 2 Department of Pharmacology, Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ, USA ● early metastasis [1]. The poor prognosis of SCLC is associated with increased proliferative rate and vascularity [2]. It is estimated that SCLC is responsible for causing 15% of global lung cancer incidence. The current approach to treat SCLC relies solely on chemotherapy, which can damage hematopoietic stem and progenitor cells (HSPCs) in bone marrow (BM) leading to chemotherapy-induced myelosuppression (CIM) [3]. CIM is characterized by reduced production of red blood cells, white blood cells, and platelets, which compromises long-term control of disease and the survival rate [4]. The effects of CIM can significantly impact patient health, increasing the risk of bleeding, fatigue, and infections, often requiring frequent transfusions and hospitalizations [5]. One mechanism to minimize myelosuppression is the reduction in treatment dose intensity; however, this reduces Medicinal Chemistry Research the effectiveness and eventually compromises disease control. The adverse effects associated with certain chemotherapeutic compounds can also be reduced with the aid of small molecules. For example, amifostine has been used to protect the kidneys from the undesired side-effects caused by cisplatin (a chemotherapeutic agent used in patients with advanced ovarian cancer) [6]. Likewise, dexrazoxane reduces risk of heart failure in women receiving doxorubicin for the treatment of breast cancer [7]. Unfortunately, there is concern that many such chemo-protectants, when given concomitantly, can diminish the effectiveness of chemotherapy. An alternative method to combat the myelotoxicity of chemotherapy includes the use of growth factors such as granulocyte-colony-stimulating factors and erythropoiesis-stimulating factors, G-CSF/EPO. Hematopoietic growth factors, a family of regulatory proteins, play a crucial role in the differentiation and survival of blood progenitor cells. Even though the commercial availability of these growth factors has attracted widespread application in cancer treatment, their use is restricted as they are expensive and not readily available to all patients in need, highlighting the need for alternative approaches that can proactively prevent CIM. Cyclin-dependent kinases (CDKs) are essential proteins that regulate key stages of the cell cycle, including DNA replication and cell division. Among the CDK family, CDK4 and CDK6 are particularly crucial in driving cells from G1 to S phase. Due to their roles in cell cycle regulation, CDK4/6 play a pivotal role in the proliferation of HSPCs in the bone marrow. Temporarily arresting the cell cycle in these cells using a potent, selective CDK4/6 inhibitor can protect blood cell counts and improve survival in mice exposed to chemotherapy or high radiation doses [8, 9]. Co-administration of a CDK4/6 inhibitor with chemotherapy agents that kill proliferating cells could widen the therapeutic window by selectively inhibiting the proliferation of normal cell and not tumor cells [10]. While many tumors rely on CDK4/6 for their growth, some tumors can grow independent of CDK4/6. These include SCLC, triple-negative breast cancer, bladder cancer, human papillomavirus (HPV)-associated head and neck cancer, and prostate cancer. The standard treatment for many patients with these tumors involves myelosuppressive chemotherapy. Temporarily arresting the cell cycle in HSPCs using a CDK4/6 inhibitor during chemotherapy could potentially protect the bone marrow and immune system from the cytotoxic effect of chemotherapy without compromising its anti-tumor efficacy. Trilaciclib (G1T28) received FDA approval in February 2021 to improve the outcome of patients with metastatic (extensive stage) SCLC by protecting bone marrow suppression during chemotherapy (Table 1). Metastatic SCLC typically refers to the spread or involvement of the cancer beyond the lung to distant organs or tissues. Trilaciclib is a first-in-class competitive CDK4/6 inhibitor that was developed by G1 Therapeutics to provide myeloprotection. Trilaciclib induces reversible G1-arrest in CDK4/6-dependent cells (such as HSPCs and lymphocytes). Due to this arrest, HSPCs are prevented from transitioning into cell cycle stages where they are susceptible to chemotherapy induced DNA damage, while CDK4/6-independent cells (such as SCLC cells) remain susceptible to the effects of the cytotoxic treatment [11]. This approach may lead to a reduced Table 1 General information on trilaciclib New Drug Highlights Drug Names Structure Indication MOA ADME/PK Major side effects Regulatory Approval Generic: Trilaciclib Other: Cosela®, G1T28 Chemical name: [2’-((5-(4-methylpiperazin-1-yl) pyridine-2-yl) amino)-7’8’-dihydro-6’H-spiro[cyclohexane-1,9’pyrazino[1’,2’:1,5]pyrrolo[2,3-d]pyrimidin]-6’-one] To reduce the occurrence of CIM in patients with metasta (...truncated)