לוח שנה משולב

Validation of hypotheses is an essential part of the scientific process. To validate novel biological targets, a range of powerful biological approaches have emerged and are being leveraged (eg CRISPR, siRNA, antisense, antibodies, etc). In addition to these biological approaches, small molecule “chemical probes” have proven to be an extremely valuable orthogonal approach for validation. Also, successful generation of a small molecule chemical probe increases the confidence that a target is druggable, and can enable demonstration of therapeutically useful effects in animal models and ultimately humans. Of note to this audience is that the majority of new biological targets that led to novel medicines were discovered in academia.
The G-INCPM at the Weizmann has established a drug discovery unit which can screen large collections of small molecules against novel biological targets or phenotypes in whole cells. A medicinal chemistry capability has recently been added to the Institute with the goal of increasing the value that will be derived from these ongoing screening efforts. The newly formed Medicinal Chemistry Unit is working closely with Biologists (at the Weizmann and other Institutes in Israel), and the High Throughput Screening Unit to interpret the output from screens, triage the output, and then optimize the most attractive hit matter. This lecture will present a definition of a “chemical probe” and our rationale for generating chemical probes. We will also discuss some of the common pitfalls in following up HTS hits, and the approaches being utilized to generate quality probes from screening campaigns.

Bone marrow (BM) retained blood forming stem cells are protected from DNA damaging agents including chemotherapy to prevent lethal infections and hematology failure. Stem cell chemotherapy resistance, requires dynamic interactions with BM stromal and endothelial cells and involves metabolic regulation of ROS, mitochondria transfer, and inhibition of NO. Leukemic stem cells initiate and maintain the disease and are the major target for clinical chemotherapy treatment. These malignant stem cells also reside in the BM and their chemotherapy resistance can lead to lethal leukemia relapse. Metabolic regulation of normal and leukemic stem cells in the bone marrow will be discussed.