PIM Kinases in Multiple Myeloma

by Selleckchem | Jul 10 2023

Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted.

Comments:

Multiple myeloma (MM) is a type of cancer characterized by the abnormal growth and accumulation of plasma cells in the bone marrow. Despite significant advances in treatment options, MM remains an incurable disease, highlighting the need for novel therapeutic approaches. One potential target for MM treatment is the PIM (Proviral insertion in murine malignancies) serine/threonine kinases, specifically the isoforms PIM1, PIM2, and PIM3.

PIM kinases play a crucial role in various biological processes, including cell growth, apoptosis, drug resistance, and immune response. Several molecules and pathways involved in myeloma tumorigenesis have been identified as downstream targets of PIM kinases. Therefore, inhibiting PIM kinases has gained scientific interest as a potential strategy for treating MM.

In recent years, several PIM kinase inhibitors have been developed and are being evaluated in clinical trials. Examples of these inhibitors include SGI-1776, AZD1208, and PIM447 (formerly LGH447). These inhibitors have shown promise in preclinical studies and are now being tested in different phases of clinical trials to assess their safety and efficacy in MM patients.

Combination therapy involving PIM kinase inhibitors and chemotherapy has demonstrated an additive cytotoxic effect in cancer cells. This approach holds potential for improving treatment outcomes in MM. However, the precise mechanisms by which PIM kinases modulate the immune microenvironment and synergize with immunomodulatory agents like lenalidomide have not been fully elucidated.

Further research is needed to better understand the interaction between PIM kinases and the immune system in MM. This knowledge could lead to the development of more effective combination strategies involving PIM kinase inhibitors and immunomodulatory agents. Additionally, efforts are underway to develop new generations of potent PIM kinase inhibitors with optimal pharmacological profiles for the treatment of MM.

In conclusion, PIM kinases represent a promising therapeutic target in MM. The development of PIM kinase inhibitors and their combination with other targeted agents, including immunomodulatory agents, holds great potential for improving treatment outcomes in MM patients. Ongoing research aims to uncover the mechanisms underlying the effects of PIM kinases and to explore new strategies to exploit PIM as a therapeutic target in malignancies, including MM.