Hsp90 Inhibitors for the Treatment of Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3' sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5' sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin-proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors.

Figure 1

Signaling pathways activated by BCR-ABL. (a) BCR-ABL activates GRB-2/SOS which in turn activates RAS. Active RAS activates RAF. Active RAF stimulates MEK1, which in turn activates ERK1/2. Activation of Ras pathway by BCR-ABL aids CML cells proliferation. On the other hand, activated GRB-2/SOS stimulates GAB2 which activates PI3-K pathway. (b) BCR-ABL phosphorylates adaptor proteins like CRK and CRKL leading to the activation of PI3-K. PI3-K phosphorylates PIP2 to PIP3 which in turn activates AKT. AKT inhibits p27 leading to CML cells proliferation. AKT phosphorylates MDM2, which in turn inhibit p53. AKT activates NFκB via phosphorylation of IKK and IkBα. AKT inhibits p-BAD. Activation of NFκB and inhibition of p53 and BAD by AKT evade apoptosis and promote CML cells survival. (c) BCR-ABL phosphorylates STAT5 which also aid in evading apoptosis of CML cells. (d) BCR-ABL phosphorylate cytoskeleton proteins resulting in increased cellular motility and reduced adhesion to extracellular matrix of bone marrow.

Figure 2

Currently available BCR-ABL specific TKIs for CML treatment. (a) First-generation TKI. ((b), (c), and (d)) Second-generation TKIs. (e) Third-generation TKI.

Figure 3

Relationship between Hsp90 and various client proteins resulting in cancer cell survival, progression, invasion, and metastasis.

Figure 4

BCR-ABL functioning in the presence and absence of Hsp90 inhibitors. (a) In CML cells, Hsp90 levels are elevated. Hence oncoprotein BCR-ABL binds to Hsp90 for stabilization and maturation. Hence, stabilized BCR-ABL then activates many signaling pathways leading to CML cells survival, progression, and malignancy. (b) Blocking Hsp90 chaperone activity by employing Hsp90 inhibitors results in BCR-ABL degradation via ubiquitin proteasome pathway.

Figure 5

Hsp90 inhibitors of microbial origin.

Figure 6

Hsp90 inhibitors of plant origin.

Figure 7

Hsp90 inhibitors of coral origin.

Figure 8

(a) Coupled enzyme assay. (b) Luciferase refolding assay.