Small Molecule Probe Development

The Broad Institute’s Therapeutics Platform can transform research projects through its robust probe development capabilities — including small-molecule screening, analysis and medicinal chemistry. Our scientists collaborate with investigators from around the world to validate new targets and identify novel probes and leads in many areas of disease biology. To date, our team has helped over 250 investigators in areas ranging from developmental biology to cancer, neurological disease, metabolic disease, infectious disease, and cardiovascular disease.

Researchers working with the Therapeutics Platform can access the Broad’s unique screening collection, currently comprising almost 500,000 molecules. Our highly-trained professional scientists can help design a screening campaign, run the screen and collaborate on post-screen analysis and lead optimization. The result: helping collaborators make better decisions to rapidly advance their science.

To date, the Broad has completed scores of small-molecule screening and chemistry optimization projects, ranging from identifying new small-molecule inhibitors to clarifying the functional role of cellular pathway components. From drafting a screening plan to assay development to primary and secondary screening, our scientists have helped advance many projects through critical decision points. They have helped identify lead candidates and devised follow-up medicinal chemistry plans, documenting all the steps and critical findings in detailed small molecule probe reports. Below is a chart that includes ongoing and completed projects that the Therapeutics Platform has enabled and in which it plays an active role.

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	Project Short Name	Probe Reports	Accept	Draft Screening Plan	Assay Dev.	Primary Screen	Re-test @Dose	Secondary Assays	Go/ No-go	Validate Hit	Draft Chemistry Plan	SAR/Analog Testing	Finalize Probe	Final Report	Close Project
1	RAS-selective lethal compounds	1 2	.	.	.	.	.	.	.	.	.	.	.	.	.
2	T. cruzi inhibiton	1 2 3	.	.	.	.	.	.	.	.	.	.	.	.	.
3	Alpha-synuclein 5' UTR inhibition	1	.	.	.	.	.	.	.	.	.	.	.	.	.
4	Alpha-synuclein 5' UTR activation	1	.	.	.	.	.	.	.	.	.	.	.	.	.
5	RAS converting enzyme inhibition		.	.	.	.	.	.	.	.	.	.	.	.	.
6	C. elegans embryogenesis modulation		.	.	.	.	.	.	.	.	.	.	.	.	.
7	Hypoxia inducible factor pathway activators	1	.	.	.	.	.	.	.	.	.	.	.	.	.
8	Modulators for redox regulation in yhe mitochondrial intermembrane		.	.	.	.	.	.
9	Chemical probes of Kaposi's sarcoma herpes virus latent infection		.	.	.	.	.	.	.	.	.	.	.	.	.
10	Augment the spread of oncolytic G47D-HSV		.	.	.	.	.	.	.	.	.	.	.
11	Chemical genetic analysis of platelet granule secretion	1 2 3	.	.	.	.	.	.	.	.	.	.	.	.	.
12	Streptokinase expression inhibitors	1 2 3	.	.	.	.	.	.	.	.	.	.	.	.	.
13	Drug discovery for bone marrow failure		.	.	.	.	.	.	.	.	.	.	.	.	.
14	Reversing antifungal drug resistance	1 2 3	.	.	.	.	.	.	.	.	.	.	.	.	.
15	LuxS quorum-sensing inhibitors		.	.	.	.	.	.	.	.	.	.	.	.	.
16	Role of Heat Shock Factor 1 in cancer: inhibition		.	.	.	.	.	.
17	Role of Heat Shock Factor 1 in cancer: induction		.	.	.	.	.	.
18	Inhibition of RanGTP/importin-beta complex		.	.	.	.	.	.	.	.	.	.	.	.	.
19	Discovery of inhibitors of anti-apoptotic protein A1	1	.	.	.	.	.	.	.	.	.	.	.	.	.
20	Intein inhibitors as potential TB drugs		.	.	.	.	.	.	.	.	.	.	.	.	.
21	Discovery of potent and selective allosteric inhibitors of GSK-3α		.	.	.	.	.	.	.	.	.	.	.	.	.
22	Small molecules with specific toxicity for breast cancer stem cells	1 2 3	.	.	.	.	.	.	.	.	.	.	.	.	.
23	Small molecule activators of DeltaFosB/ FosB		.	.	.	.	.	.	.	.	.	.	.	.	.
24	Suppressors of cytokine-induced beta-cell apoptosis	1	.	.	.	.	.	.	.	.	.	.	.	.	.
25	Elucidation of physiology of non-replicating, drug-tolerant M. tuberculosis	1	.	.	.	.	.	.	.	.	.	.	.
26	Elucidation of physiology of replicating and non-replicating, drug-tolerant M. tuberculosis	*	.	.	.	.	.	.
27	Elucidation of physiology of transition-state, drug-tolerant M. tuberculosis		.	.	.	.	.	.
28	Inhibitors of histone demethylase GASC-1		.	.	.
29	Potent and selective inhibitors of GSK-3β	1	.	.	.	.	.	.	.	.	.	.	.	.
30	Small molecule inhibitors of SUMOylation		.	.	.	.	.	.		.	.	.	.	.
31	Inhibitors of hedgehog auto-processing		.	.	.	.	.	.		.	.	.	.	.
32	Inhibitors of the prion 5’UTR		.	.	.	.	.	.	.	.	.	.	.	.	.
33	Identification of small molecule inhibitors of MITF	1	.	.	.	.	.	.	.	.	.	.	.	.
34	Identification of small molecule activators of MITF		.	.	.	.	.	.
35	Inhibitors of pyoverdine production	1	.	.	.	.	.	.	.	.	.	.	.	.
36	HDL scavenger receptor (SRBI): inhibitor	1 2 3	.	.	.	.	.	.	.	.	.	.	.	.
37	HDL scavenger receptor (SRBI): activator		.	.	.	.	.	.		.	.	.	.	.
38	Twin arginine translocation (TAT) pathway inhibition		.	.	.	.	.	.	.	.	.	.	.	.
39	Development of Cdk5 inhibitor		.	.	.	.	.	.	.	.	.	.	.	.	.
40	Inhibitors of galactofuranose residues (UGM)		.	.	.	.	.	.		.	.	.	.	.
41	Discovery of anti-fungal small molecules (Rtt109)		.	.	.	.	.	.		.	.	.	.	.
42	Small-molecule targeting of CFTR: PDZ trafficking interactions		.	.	.	.	.	.	.	.	.	.	.	.	.
43	Visual cycle inhibitors (RBP4)		.	.	.	.	.	.		.	.	.	.	.
44	Antagonists of Vif dimerization		.	.	.	.
45	Supressors of statin induced myotoxicity		.	.	.	.	.
46	NFAT signaling and Down syndrome		.	.	.	.	.	.
47	Inhibitors of Keap1-Nrf2 interaction	1	.	.	.	.	.	.	.	.	.	.
48	Identification of malaria Hsp40 chaperone inhibitors		.	.	.	.	.	.
49	Identifying species-specific anti-malarial Hsp90 inhibitors		.	.	.	.	.	.	.	.	.	.	.	.	.
50	Epstein-Barr virus LMP-1 mediated oncogenicity		.	.	.	.	.	.	.	.	.	.
51	Inhibitors of Kaposi’s Sarcoma Herpes virus (LANA-C)		.	.	.	.	.	.		.	.	.
52	Yersinia pestis topoisomerase I Inhibitors		.	.	.	.	.	.		.	.	.
53	Inhibitors of ATP-dependent chromatin remodeling		.	.	.	.
54	Modulators of quorum sensing in Vibrio cholera	* *	.	.	.	.	.
55	Schnurri-3 inhibitors: specific inducers of adult bone formation		.	.	.	.	.	.
56	Inhibitors of protein disulfide isomerase	* *	.	.	.	.	.	.
57	Compounds modulating PGC-1a acetylation and oxidative metabolic function		.	.	.	.
58	Molecules that overcome differentiation arrest in acute myeloid leukemia		.	.	.	.	.	.
59	Small molecule inhibitors of microRNA miR-122 function		.	.	.	.	.	.
60	Small molecule activators of microRNA miR-122 function		.	.	.	.	.	.
61	Inhibitors of fatty acid adenylating enzymes		.	.	.	.	.				.	.
62	Inhibitors of N-linked glycosylation		.	.	.	.	.	.
63	Antiviral drug screening against dengue virus		.	.	.
64	Anti-fungal, single agent	1	.	.	.	.	.	.	.	.	.	.	.	.
65	Identification of agents that induce E-selectin in human endothelial cells		.	.	.
66	Modulators of the fidelity of start codon recognition in eukaryotes		.	.	.	.	.				.	.
67	Inhibitors of c-Myc/Mac dimerization and DNA binding		.	.	.
68	Modulators of PAS/coactivator interactions		.	.	.	.	.	.
69	Inhibition of glycoprotein biosynthesis in Gram-negative pathogens		.	.	.
70	Discovery and evaluation of fungicidal anti-cryptococcal molecules		.	.	.	.	.	.
71	Inhibition of the MLL-AF4-AF9 interaction in pediatric leukemia		.	.	.	.	.	.
72	Genomics-guided characterization of iPS cells from common mental illness		.	.
73	Identification of inhibitors of RAD54		.	.	.	.	.	.
74	Inhibitors of BioA: An enzyme involved in biotin biosynthesis		.	.	.	.	.	.
75	Inhibition of thiol isomerases during thrombus formation		.	.	.	.	.
76	Chemical probes of the astroglial potassium channel Kir4.1		.	.
77	Inhibitors of STK-33 kinase activity	1	.	.	.	.	.	.	.	.	.	.	.	.
78	Novel chemotypes for T. cruzi	1			.	.	.	.	.	.	.	.	.	.
79	Broad-range inhibitors of human immunodeficiency virus entry				.	.
80	Inhibitors of the ETS transcription factor rearrangement EWS/FLI in Ewing's Sarcoma				.	.
81	Inducers of X-reactivation and reprogramming of iPS cells
82	Inhibitors of endoplasmic reticulum aminopeptidase 1 (ERAP-1)
83	Identification of CFTR modulators using human bronchial epithelial cells
84	Inhibitors of RAD52 targeting BRCA2-deficient cancer				.	.
85	Activators of the two-pore-domain potassium channel, TREK-2
86	Inhibitors of the two-pore-domain potassium channel, TREK-2
87	Selective inhibitors of human HSF2
88	Inhibitors of fibronbectin fibrillogenesis
89	Inhibitors of sirtuin 5 (SIRT5)				.	.
90	Inhibitors of S100A4/ myosin interaction involved in tumor metastasis				.	.
91	Inhibitors of caspase-6 for neurodegenerative diseases
92	Inhibitors of histone methyltransferase NSD2
93	Inhibitors of PAX8 for targeting ovarian cancer
94	Novel molecular pathways regulating glucose-dependent insulin secretion
95	Inhibitors of bacterial protein synthesis with novel modes of action
96	Inhibitors of C. Difficile toxins
97	Modulators of CaV1.3 Ca2+ regulation

Updated: 02/28/2013

.	In progress
.	Complete
.	Project continued
.	Project stopped
.	Not applicable
1	Probe report available
1	Probe report submitted
*	Probe report in progress