Small molecule inhibitor targets several proteins to cure for acute leukemia

Small molecule inhibitor targets several proteins to cure for acute leukemia

Acute myeloid leukemia is one of the most aggressive cancers. While other cancers have benefitted from new treatments, there has been no encouraging news for most leukemia patients for the past 40 years.

As published in the journal Cell, a research team has developed a new biological drug with a cure rate of 50% for lab mice with acute leukemia.

Leukemia produce a variety (and a high quantity) of proteins that together provide leukemic cells with rapid growth and death protection from chemotherapy.

To date, most of the biological cancer drugs used to treat leukemia target only individual leukemic cell proteins. However, during "targeted therapy" treatments, leukemic cells quickly activate their other proteins to block the drug. The result is drug-resistant leukemic cells which quickly regrow and renew the disease.

However, the new drug developed by the team functions like a cluster bomb. It attacks several leukemic proteins at once, making it difficult for the leukemia cells to activate other proteins that can evade the therapy. Further, this single molecule drug accomplishes the work of three or four separate drugs, reducing cancer patients need to be exposed to several therapies and to deal with their often unbearable side-effects.

Mechanistically, CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Authors describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity.

Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. Researchers identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes.

Authors show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in cell culture and AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.

"We were thrilled to see such a dramatic change even after only a single dose of the new drug. Nearly all of the lab mice's' leukemia signs disappeared overnight," shared the senior author.

BioTheryX recently bought the rights to this promising drug from HU's technology transfer company Yissum. Together with Ben-Neriah's research team, they are now applying for FDA approval for phase I clinical studies.

https://www.cell.com/cell/fulltext/S0092-8674(18)30973-5
 
https://www.eurekalert.org/pub_releases/2018-08/thuo-fft082418.php

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