Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic

Al-Hussaini, Muneera; DiPersio, John F.

doi:10.1586/17474086.2014.932687

Cited by 22 publications

(27 citation statements)

References 348 publications

(272 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently, chemotherapy for AML can achieve remission in 60 to 80% of patients less than 60 years of age [4]. Most, however, relapse with cancers that are treatment-resistant within 2-3 years, and 5-year survival rates are as low as 30% [5, 6]. Unfortunately, treatment with RA does not induce differentiation in AML, only apoptosis or inhibition of proliferation [7].…”

Section: Introductionmentioning

confidence: 99%

RRD-251 enhances all-trans retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

et al. 2016

View full text Add to dashboard Cite

All-trans-retinoic acid (RA) is known to induce terminal granulocytic differentiation and cell cycle arrest of HL-60 cells. Responding to an RA-induced cytosolic signaling machine, c-Raf translocates to the nucleus, providing propulsion for RA-induced differentiation. This novel mechanism is not understood, but presumably reflects c-Raf binding with nuclear gene regulatory proteins. RRD-251 is a small molecule that prevents the interaction of c-Raf and RB, the retinoblastoma tumor suppressor protein. The involvement of c-Raf and RB in RA-induced differentiation motivates interest in the effects of combined RA and RRD-251 treatment on leukemic cell differentiation.We demonstrate that RRD-251 enhances RA-induced differentiation. Mechanistically, we find that nuclear translocated c-Raf associates with pS608 RB. RA causes loss of pS608 RB, where cells with hypophosphorylated S608 RB are G0/G1 restricted. Corroborating the pS608 RB hypophosphorylation, RB sequestration of E2F increased with concomitant loss of cdc6 expression, which is known to be driven by E2F. Hypophosphorylation of S608 RB releases c-Raf from RB sequestration to bind other nuclear targets. Release of c-Raf from RB sequestration results in enhanced association with GSK-3 which is phosphorylated at its S21/9 inhibitory sites. c-Raf binding to GSK-3 is associated with dissociation of GSK-3 and RARα, thereby relieving RARα of GSK-3 inhibition. RRD-251 amplifies each of these RA-induced events. Consistent with the posited enhancement of RARα transcriptional activity by RRD-251, RRD-251 increases the RARE-driven CD38 expression per cell. The RA/c-Raf/GSK-3/RARα axis emerges as a novel differentiation regulatory mechanism susceptible to RRD-251, suggesting enhancing RA-effects with RRD-251 in therapy.

show abstract

Section: Introductionmentioning

confidence: 99%

RRD-251 enhances all-trans retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Small molecule inhibitors have the advantage of being able to target cell surface ligand receptors and intracellular proteins that promote the downstream signaling pathway for cell growth and metastatic disease. Targeted therapy with small molecule inhibitors, such as tyrosine kinase inhibitors (TKIs) for t(9;22) BCR-ABL gene fusion for Chronic Myeloid Leukemia (CML) or all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APML), have already proven to be successful [32]. The challenge in identifying potential targets in AML has been its heterogeneous genetic and molecular make up, with frequent evolution of the driver mutations at disease onset and progression.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

New and Emerging Targeted Therapies for Pediatric Acute Myeloid Leukemia (AML)

Chen

Glasser

2020

Children

View full text Add to dashboard Cite

The relapse rate for children with acute myeloid leukemia (AML) remains high despite advancements in risk classification, multi-agent chemotherapy intensification, stem cell transplantation, and supportive care guidelines. Prognosis for this subgroup of children with relapsed/refractory AML remains poor. It is well known that the ceiling of chemotherapy intensification has been reached, limited by acute and chronic toxicity, necessitating alternative treatment approaches. In the last several years, our improved understanding of disease biology and critical molecular pathways in AML has yielded a variety of new drugs to target these specific pathways. This review provides a summary of antibody drug conjugates (ADCs), small molecule inhibitors, and tyrosine kinase inhibitors with an emphasis on those that are currently under clinical evaluation or soon to open in early phase trials for children with relapsed/refractory AML.

show abstract

“…Recent findings on the use of small molecules targeting LSCs for their eradication in AML are reviewed by Al-Hussaini and DiPersio [35]. Although recent success in expanding HSCs ex vivo has been achieved, maintaining LSCs ex vivo remains a challenge.…”

Section: Small Molecule Regulation Of Leukemic Stem Cellsmentioning

confidence: 99%