Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, , BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors. In this review, the function of the different antiapoptotic BCL2-proteins and their role in solid tumours will be discussed. In addition, a comprehensive analysis of current small molecules targeting these antiapoptotic BCL2-proteins (e.g., ABT-737, ABT-263, ABT-199, TW-37, sabutoclax, obatoclax, and MIM1) will be provided including a discussion of the results of any clinical trials. This analysis will summarise the potential of BCL2-inhibitors for the treatment of solid tumours and will unravel novel approaches to utilise these inhibitors in clinical applications. 1. Mechanisms of Apoptosis Evasion of cell death or apoptosis is a key hallmark of cancer [1]. Generally, cells can die by apoptosis, a form of programmed cell death, or after acute injury by necrosis and cell lysis, which initiates an inflammatory response. Apoptosis was first described as a unique process associated with typical morphological changes by Carl Vogt as early as 1842 and was named apoptosis in 1972 [2]. It is a common property of multicellular organisms and is present in virtually all cell types throughout the body. Apoptosis plays a fundamental role in physiological processes, especially in mammalian development and the immune system [3, 4]. In addition, apoptosis represents a major barrier to cancer cells that must be circumvented. Therefore, many tumours acquire resistance to apoptosis through a variety of strategies. The most commonly occurring loss of a proapoptotic regulator involves the p53 tumour suppressor gene [5]. In addition to the activation of proapoptotic factors, resistance to apoptosis is often due to upregulation of antiapoptotic factors. Thus, a number of genes that encode components of the apoptotic machinery are directly targeted by activating or inactivating genetic lesions in cancer cells. In many tumours, deregulation of cell death underlies drug resistance and is a major reason for failure of conventional anticancer therapy. Upon activation, apoptosis unfolds in a precisely organised series of steps,
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