[Federal Register Volume 79, Number 121 (Tuesday, June 24, 2014)]
[Notices]
[Pages 35755-35756]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-14719]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Center for Advancing Translational Sciences (NCATS): 
Cooperative Research and Development Agreement (CRADA) and Licensing 
Opportunity for Small Molecule Inhibitors of the Human USP1/UAF1 
Complex(1) for the Treatment of Cancer

SUMMARY: The National Center for Advancing Translational Sciences 
(NCATS) and its collaborator, the University of Delaware, are seeking 
Cooperative Research and Development Agreement (CRADA) partners to 
collaborate in the final stages of lead optimization, evaluation and 
preclinical development of a novel series of selective and potent 
small-molecule inhibitors of the human USP1/UAF1 complex(1) for the 
treatment of cancer. Interested potential CRADA partners will receive 
detailed information about the project after signing a confidential 
disclosure agreement (CDA) with NCATS and University of Delaware.

DATES: Interested candidate partners must submit a statement of 
interest and capability to the NCATS point of contact before July 24, 
2014 for consideration. Guidelines for the preparation of a full CRADA 
proposal will be communicated shortly thereafter to all respondents 
with whom initial confidential discussions will have established 
sufficient mutual interest. CRADA applications submitted after the due 
date may be considered if a suitable CRADA collaborator has not been 
identified by NIH and its collaborator, the University of Delaware, 
among the initial pool of respondents. Licensing of background 
technology related to this CRADA opportunity is also available to 
potential collaborators.

ADDRESSES: Questions about licensing opportunities of related 
background technology should be addressed to Jenny Wong, M.S., Senior 
Licensing and Patenting Manager, Office of Technology Transfer, NIH, 
6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804, 
Telephone: (301) 435-4633; Email: [email protected]. Respondents 
interested in licensing will be required to submit an ``Application for 
License to Public Health Service Inventions.'' An executed CDA will be 
required to receive copies of the patent applications.

FOR FURTHER INFORMATION CONTACT: Further details of this CRADA 
opportunity and statement of interest please contact Lili Portilla, 
M.P.A., Director of Strategic Alliances, National Center for Advancing 
Translational Sciences, NIH, 9800 Medical Center Drive, Room 311, 
Rockville, MD 20850; Telephone (301) 217-2589; Email: [email protected] or 
Dr. Krishna Balakrishnan, Senior Technology Transfer Manager, NCATS, 
Telephone: (301) 217-2336; Email: [email protected].

SUPPLEMENTARY INFORMATION: Ubiquitin-specific proteases (USPs) have in 
recent years emerged as a promising therapeutic target class in the 
ubiquitin-proteasome system (UPS). Velcade[supreg] (bortezomib), a 
small molecule proteasome inhibitor, has established the ubiquitin-
proteasome system as a valid target for anticancer treatment. However, 
proteasome inhibitors in general suffer from a narrow therapeutic index 
and acquired resistance. A promising alternative to proteasome 
inhibition has been to target the enzymes upstream of proteasome-
mediated protein degradation, i.e. the ubiquitin ligases and 
deubiquitinating enzymes (DUBs), to generate more specific, less toxic 
therapeutic agents.
    The advantage of inhibiting DUB lies in the specificity of 
therapeutic intervention that can lead to better efficacy and reduced 
side effects. It has become clear that the DUB activities are 
indispensable for the normal cellular functions. Abnormal cellular 
expression of DUBs or the loss of function due to mutation in certain 
DUB genes have been linked to various human diseases(2, 3). Among the 
five DUB subfamilies, ubiquitin-specific protease (USP) is emerging as 
promising targets for pharmacological intervention because of their 
connection to many human diseases, including prostate, colon and breast 
cancer, pediatric acute lymphoblastic leukemia, and familial 
cylindromatosis(2, 4). From the past successes in targeting proteases 
with small molecule antagonists, it is expected that efforts of 
targeting human USPs will lead to potent and specific therapeutic 
agents.
    The human ubiquitin-specific protease 1 (or USP1) occupies a 
special position because it has been implicated in DNA damage response 
in higher vertebrates and humans. Previous studies showed that 
disruption of USP1 in chicken DT40 cells resulted in increased 
sensitivity to DNA crosslinkers(5) and knockout of the murine USP1 gene 
in a mouse model resulted in hypersensitivity to mitomycin C(6). 
Previously we have demonstrated that inhibiting the cellular activity 
of human USP1 by

[[Page 35756]]

pharmacologically active small molecules sensitized cisplatin-resistant 
non-small cell lung cancer (NSCLC) cells to DNA crosslinking agent(77). 
Thus, USP1 inhibitors hold promise in combination therapy with the 
existing anti-cancer drugs to improve the efficacy and lower the toxic 
effect of the existing drugs.
    More recently we have developed small molecules that target the 
USP1/UAF1 DUB complex(1). These compounds were identified via a high-
throughput screen and subjected to medicinal chemistry optimization, 
leading to one of the most potent and selective DUB inhibitors reported 
to date. Moreover, the inhibitors act synergistically with cisplatin, a 
DNA damaging anti-cancer drug, to overcome chemoresistance and enhance 
cytotoxicity. These results suggest the inhibitors may also improve the 
efficacy and potency of other commonly prescribed chemotherapeutic 
agents that are known to induce DNA damage. Furthermore the USP1/UAF1 
small molecule inhibitors also hold promise in the single-agent 
therapy.
    Under the CRADA, the chemical series will be further characterized 
and optimized to address specific aspects of this target product 
profile. The CRADA scope will also include studies beyond candidate 
selection including all aspects of preclinical studies such as toxicity 
studies, xenograft studies and chemistry GMP scale up of selected 
compounds and manufacture of control leading to a successful 
investigational new drug (IND) application. Collaborators should have 
experience in pre-clinical development of small molecules with a focus 
on cancer and a track record of successful submission of IND 
applications to the FDA.
    The full CRADA proposal should include a capability statement with 
a detailed description of (1) collaborator's expertise in the areas of 
modulation of small molecule physicochemical and pharmacokinetic 
properties; (2) expertise in formulation of small molecules and ability 
to manufacture sufficient quantities of chemical compounds according to 
FDA guidelines and under Good Manufacturing Practice (GMP); (3) 
expertise with oncology and/or other diseases which may benefit from 
USP1/UAF1 inhibition; (4) expertise in regulatory affairs, particularly 
at the IND filing and early clinical trial stages; (5) collaborator's 
ability to support, directly or through contract mechanisms, and 
ability, upon the successful completion of relevant milestones, to 
support the ongoing pharmacokinetics and biological studies, long term 
toxicity studies, process chemistry and other pre-clinical development 
studies needed to obtain regulatory approval of a given molecule so as 
to ensure a high probability of eventual successful commercialization; 
(6) collaborator's ability to provide adequate funding to support some 
of the project's pre-clinical studies.

Publications

1. Liang, Q., Dexheimer, T. S., Zhang, P., Rosenthal, A. S., 
Villamil, M. A., You, C., Zhang, Q., Chen, J., Ott, C. A., Sun, H., 
Luci, D. K., Yuan, B., Simeonov, A., Jadhav, A., Xiao, H., Wang, Y., 
Maloney, D. J., and Zhuang, Z. (2014) A selective USP1-UAF1 
inhibitor links deubiquitination to DNA damage responses, Nature 
chemical biology 10, 298-304.
2. Singhal, S., Taylor, M. C., and Baker, R. T. (2008) 
Deubiquitylating enzymes and disease, BMC Biochem 9 Suppl 1, S3.
3. Reyes-Turcu, F. E., Ventii, K. H., and Wilkinson, K. D. (2009) 
Regulation and cellular roles of ubiquitin-specific deubiquitinating 
enzymes, Annu Rev Biochem 78, 363-397.
4. Hussain, S., Zhang, Y., and Galardy, P. J. (2009) DUBs and 
cancer: the role of deubiquitinating enzymes as oncogenes, non-
oncogenes and tumor suppressors, Cell Cycle 8, 1688-1697.
5. Oestergaard, V. H., Langevin, F., Kuiken, H. J., Pace, P., 
Niedzwiedz, W., Simpson, L. J., Ohzeki, M., Takata, M., Sale, J. E., 
and Patel, K. J. (2007) Deubiquitination of FANCD2 is required for 
DNA crosslink repair, Mol Cell 28, 798-809.
6. Kim, J. M., Parmar, K., Huang, M., Weinstock, D. M., Ruit, C. A., 
Kutok, J. L., and D'Andrea, A. D. (2009) Inactivation of murine Usp1 
results in genomic instability and a Fanconi anemia phenotype, Dev 
Cell 16, 314-320.
7. Chen, J., Dexheimer, T. S., Ai, Y., Liang, Q., Villamil, M. A., 
Inglese, J., Maloney, D. J., Jadhav, A., Simeonov, A., and Zhuang, 
Z. (2011) Selective and Cell-Active Inhibitors of the USP1/UAF1 
Deubiquitinase Complex Reverse Cisplatin Resistance in Non-small 
Cell Lung Cancer Cells, Chemistry & biology 18, 1390-1400.

Patent Status

US Provisional Patent Application No. 61/747,052 entitled ``Inhibitors 
of the USP/UAF1 Deubiquitinase Complexes and Uses Thereof'' filed 
December 28, 2012; Inventors: Thomas Dexheimer (NCATS), Ajit Jadhav 
(NCATS), Qin Liang (University of Delaware), David Maloney (NCATS), 
Andrew Rosenthal (NCATS), Anton Simeonov (NCATS), Zhihao Zhuang 
(University of Delaware) NIH Ref. No.: E-043-2013/0-US-01.
PCT Application No. PCT/US2013/077804 entitled, ``Inhibitors of the 
USP/UAF1 Deubiquitinase Complexes and Uses Thereof'' filed December 26, 
2013 Inventors: Thomas Dexheimer (NCATS), Ajit Jadhav (NCATS), Qin 
Liang (University of Delaware), Diane Luci (NCATS), David Maloney 
(NCATS), Andrew Rosenthal (NCATS), Anton Simeonov (NCATS), Zhihao 
Zhuang (University of Delaware) NIH Ref. No.: E-043-2013/0-PCT-02.

    Dated: June 12, 2014.
Christopher P. Austin,
Director, National Center for Advancing Translational Sciences, 
National Institutes of Health.
[FR Doc. 2014-14719 Filed 6-23-14; 8:45 am]
BILLING CODE 4140-01-P