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Anticancer agents targeting proliferating cell populations in tumor as well as in normal tissues can lead to a number of side effects including hematotoxicity, a common dose-limiting toxicity associated with oncology drugs. Myelosuppression, regarded as unacceptable for other therapeutic indications, is considered a clinical risk also for new targeted anticancer drugs acting specifically on tumor cells. Thus, it becomes important not only to evaluate the potential toxicity of such new therapeutics to human hematopoietic tissue during preclinical development but also to anticipate this liability in early drug discovery. This could be achieved by using in silico models to guide the design of new lead compounds and the selection of analogs with reduced myelosuppressive potential. Hence, the purpose of this study was to develop computational models able to predict the potential myelotoxicity of drugs from their chemical structure. The data set analyzed included 38 drugs. The structural diversity and the drug-like space covered by these molecules were investigated using the ChemGPS methodology. Two sets of potentially relevant descriptors for modeling myelotoxicity (i.e., 3D Volsurf+ and 2D structural and electrotopological E-states descriptors) were selected and a Principal Component Analysis was carried out on the entire set of data. The first two PCs were able to discriminate the highest from the least myelotoxic compounds with a total accuracy of 95%. Then, a quantitative PLS model was developed by correlating a selected subset of in vitro hematotoxicity data with Volsurf+ descriptors. After variable selection, the PLS analysis resulted in a one-latent-variable model with r(2) of 0.79 and q(2) of 0.72. The inclusion of 2D descriptors in the PLS analysis improved only slightly the robustness and quality of the model that predicted the pIC(50) values of 21 drugs not included in the model with a RMSEP of 0.67 and a squared correlation coefficient (r(0)(2)) of 0.70. Furthermore, in order to investigate whether the highly myelotoxic compounds are characterized by common structural features, which should be taken into consideration in the design of new candidate drugs, the entire data set was analyzed using GRIND toxicophore-based descriptors. One toxicophore emerged from the interpretation of the model. The toxicophore elements, at least determined by the molecules used in this study, are a pattern of H-bond acceptor groups, presence of a H-bond donor and H-bond acceptor regions at ∼15 Å distance and a hydrophobic and H-bond acceptor interacting regions separated by a distance of ∼12.4 Å. Moreover, the dimensions of the molecule play a role in its recognition as a myelotoxic compound.

Currently, several protein kinase-modulating compounds have received market approval across a range of diverse therapeutic indications. Furthermore, a large number of chemical and biological protein kinase-modulating compounds are undergoing testing at the preclinical and clinical level. Protein kinases are both major pharmacological targets and diagnostically useful. Progression of kinase modulators toward clinically viable therapies is aided by a reversible mechanism of action, short treatment durations and patient-compliant administration routes. However, the physiological role and essential functional activity of protein kinases in many organs and tissues complicates, to different extents, the development of useful, highly potent protein kinase modulators. In this review, we will highlight common problems in the development of these compounds and lessons learned from the extensive preclinical and clinical characterization of some key protein kinase modulators, some of which have either entered and successfully completed clinical trials or have been abandoned as a consequence of unacceptable toxicity issues. We will ultimately explore how molecular profiling tools combined with histopathological endpoints can be adopted to address and further understand these toxicities in humans and understand their relevance and characterization when identified during early animal experiments.

The design, synthesis, in vitro and in vivo activities of novel alpha-bromoacrylic derivatives of distamycin A, modified at the amidino moiety by the replacement with basic or non-basic groups are reported. In spite of the relevance of these modifications of distamycin frame, the new derivatives are potent cytotoxics. The presence of the amidino moiety, is, therefore; not an absolute requirement for the activity. In particular due to a favorable myelotoxicity/cytotoxicity ratio, guanidino derivative PNU 166196 was selected for clinical development.

Purpose: MMDX [3'-deamino-3'-[2(S)-methoxy-4-morpholinyl] doxorubicin], an anthracycline derivative active in vitro and in vivo against multidrug-resistant tumors, is currently under investigation in phase I clinical trials. In vivo it is metabolically activated, resulting in more cytotoxic compounds. We determined in vitro the toxic concentration of a 1-h period of exposure to doxorubicin (DX), MMDX, and bioactivated MMDX on hematopoietic progenitors and tumor cell lines., Methods: DX and MMDX were tested on both bone marrow- (BM) and cord blood (hCB)-derived clonogenic cells, whereas the metabolites were tested on hCB only. All substances were tested on seven tumor cell lines., Results: BM cells proved to be twice as sensitive as hCB cells to cytotoxics, and MMDX was twice as toxic as DX against hCB cells; MMDX activated with normal rat-liver microsomes and with dexamethasone-induced rat microsomes were, respectively, 70 and 230 times more toxic than MMDX. A comparison of the cytotoxic concentrations on hematopoietic progenitors and tumor cells, revealed that DX and MMDX had 5-fold stronger activity on tumor cell lines than on granulocyte/macrophage colony-forming cells (GM-CFCs), whereas bioactivated MMDX showed comparable cytotoxicity against tumor cells and hematopoietic progenitors., Conclusions: MMDX metabolites are very potent but display a lower degree of tumor selectivity than MMDX. Strategies to reduce MMDX metabolization should be developed to optimize the therapeutic index of this new anthracycline.