John 'Jay' Schneekloth Jr., Ph.D.

John 'Jay' Schneekloth Jr., Ph.D.
Senior Investigator
Head, Chemical Genetics Section

My laboratory uses chemical biology approaches to identify and study small molecules that bind to RNA.  

Link to additional information about Dr. Schneekloth’s research.

Areas of Expertise

1) RNA-binding small molecules 2) chemical biology 3) organic chemistry 4) RNA biology

Contact Info

John 'Jay' Schneekloth Jr., Ph.D.
Center for Cancer Research
National Cancer Institute
Building 538, Room 249
Frederick, MD 21702-1201
Ph: 301-228-4620

Targeting RNA with Druglike Small Molecules

The identification of selective RNA- and DNA-binding small molecules has been a longstanding challenge for chemical biology. Recent studies have demonstrated that while more than 85% of the human genome is transcribed into RNA, just 3% of those transcripts code for protein sequences.  Coupled with the discovery that non-coding functions of RNA can drive disease, RNA has emerged as an intriguing but challenging therapeutic target for small molecules. In particular, regulatory nucleic acids that drive the expression of clinically important but so-called "undruggable" proteins such as c-MYC and KRAS respresent targets of interest.  Our laboratory aims to advance the field of targeting RNA with druglike small molecules on multiple fronts.  We use an integrated approach, including chemical biology, medicinal chemistry, structural biology, and functional genomics to understand and control RNA targets with small molecules. WIth respect to discovery, we have developed a small molecule microarray (SMM) high throughput screening platform that allows us to rapidly identify and profile the RNA-binding properties of small molecules.  We use hits from this screening platform as the basis for development of small molecule probes that selectively target RNA. This work has led to the discovery that druglike compounds are suitable starting points for inhibitor discovery efforts for RNA targets, while driving fundamental advances in understanding RNA-small molecule recognition.  Together, this work aims to develop RNA-binding small molecule probes to improve our understanding of RNA-mediated processes and disease states, particularly for cancers with no existing treatment options.

NIH Scientific Focus Areas:
Cancer Biology, Chemical Biology, Molecular Biology and Biochemistry, Molecular Pharmacology, RNA Biology
  1. Yang M, Schneekloth JS Jr.
    Trends Pharmacol Sci. 40(7): 447-8, 2019. [ Journal Article ]
  2. Connelly CM, Numata T, Boer RE, Moon MH, Sinniah RS, Barchi JJ, Ferré-D'Amaré AR, Schneekloth JS Jr.
    Nat Commun. 10(1): 1501, 2019. [ Journal Article ]
  3. Boer RE, Schneekloth JS Jr.
    Cell Chem Biol. 25(12): 1437-38, 2018. [ Journal Article ]
  4. Calabrese DR, Chen X, Leon EC, Gaikwad SM, Phyo Z, Hewitt WM, Alden S, Hilimire TA, He F, Michalowski AM, Simmons JK, Saunders LB, Zhang S, Connors D, Walters KJ, Mock BA, Schneekloth JS Jr.
    Nat Commun. 9(1): 4229, 2018. [ Journal Article ]
  5. Calabrese DR, Zlotkowski K, Alden S, Hewitt WM, Connelly CM, Wilson RM, Gaikwad S, Chen L, Guha R, Thomas CJ, Mock BA, Schneekloth JS Jr.
    Nucleic Acids Res. 46(6): 2722-32, 2018. [ Journal Article ]

Dr. Schneekloth received his undergraduate degree from Dartmouth College in 2001 where he worked with Prof. Gordon Gribble. He then moved to Yale University and obtained a Ph.D. from the chemistry department with Prof. Craig Crews in 2006. As a graduate student he studied natural product total synthesis and developed the first cell-permeable PROTAC molecules. He then pursued an NIH postdoctoral fellowship with Prof. Erik Sorensen at Princeton University where he worked on the development of a new multicomponent reaction and the application of this reaction to the synthesis of analgesic natural products. He returned to Yale in 2009 where he worked as a medicinal chemist at the Yale Small Molecule Discovery Center. In 2011, Dr. Schneekloth joined NCI where his research involves using synthetic chemistry and high throughput chemical biology approaches to develop chemical probes of RNA, with a particular emphasis on targeting RNA with druglike small molecules.

Name Position
Sumirtha Balaratnam Ph.D. Postdoctoral Fellow (Visiting)
Christopher Fullenkamp Ph.D. Postdoctoral Fellow (CRTA)
Deondre Jordan Postbaccalaureate Fellow (CRTA)
Xiao Liang Ph.D. Postdoctoral Fellow (Visiting)
Shaifaly Parmar Ph.D. Postdoctoral Fellow (Visiting)
Curran Rhodes Ph.D. Postdoctoral Fellow (CRTA)
Emily Nhu Hao Tran Postbaccalaureate Fellow (CRTA)
Mo Yang Ph.D. Postdoctoral Fellow (Visiting)
Kamyar Yazdani Postbaccalaureate Fellow (CRTA)