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Developing small molecule inhibitors of TLR8 for treatment of rheumatoid arthritis

Award Number: R44AI100376
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2012
PERIOD OF PERFORMANCE END DATE: 01/31/2018

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Developing small molecule inhibitors of TLR8 for treatment of rheumatoid arthritis - ¿ DESCRIPTION (provided by applicant): Autoimmune diseases like rheumatoid arthritis (RA) develop when the immune response targets self- antigens, leading to inflammation and tissue destruction. There is now considerable evidence that recognition of self nucleic acids through toll-like receptors (TLRs) can contribute significantly to sterile inflammation and autoimmunity, with the clearest example being the role played by TLR9 and TLR7 in the pathogenesis of systemic lupus erythematosus (SLE). Similarly, TLR8, a potent stimulator of inflammatory cytokines such as IL6 and TNF-a, has a strong association with RA and other autoimmune indications. However, the lack of useful animal models, a consequence of the different ligand specificity of human TLR8 and its rodent orthologs, has proven to be a major limitation in the study of TLR8 function and the identification of possible therapeutics. We have developed new tools, including in vivo animal models that have allowed us to better understand the biology of TLR8 in autoimmunity and specifically for a role of TLR8 signaling in RA. We propose to use these tools to identify a lead small molecule antagonist for developing a therapeutic for TLR8- mediated autoimmunity. The key objective of this Phase II proposal is to identify lead small-molecule antagonists of human TLR8 from a set of candidate hits that we have identified through high-throughput screening with funding from a Phase I SBIR. The principal activities will include: 1). Advancing hits and identifying lead compounds with specific and improved huTLR8 antagonist activity through a process of iterative computer-aided drug design with structure-based modeling and cell-based activity; 2). Determining the activity of the lead candidates in TLR8-dependent RA mouse model; 3). Conducting preliminary toxicology of lead compounds to support IND-enabling studies If successful, we anticipate obtaining a small number of lead small molecule candidates that inhibit TLR8 and have sufficient attributes (e.g., potency) to move into IND enabling studies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = -$268,662 )
2018	2017	DYNAVAX TECHNOLOGIES CORPORATION	2929 7TH ST STE 100	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	002	4	6/19/2018	NON-COMPETING CONTINUATION	-$343,664
2018	2017	DYNAVAX TECHNOLOGIES CORPORATION	2929 7TH ST STE 100	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	4	11/24/2017	NON-COMPETING CONTINUATION	$16,295
2018	2016	DYNAVAX TECHNOLOGIES CORPORATION	2929 7TH ST STE 100	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	3	12/22/2017	COMPETING CONTINUATION	$58,707
														Subtotal = -$268,662

Issue Date FY: 2017 ( Subtotal = $406,490 )
2017	2017	DYNAVAX TECHNOLOGIES CORPORATION	2929 7TH ST STE 100	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	4	1/27/2017	NON-COMPETING CONTINUATION	$406,490
														Subtotal = $406,490

Issue Date FY: 2016 ( Subtotal = $530,775 )
2016	2016	DYNAVAX TECHNOLOGIES CORPORATION	2929 7th St Ste 100	Berkeley	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	3	2/11/2016	COMPETING CONTINUATION	$530,775
2016	2016	DYNAVAX TECHNOLOGIES CORPORATION	717 POTTER STREET SUITE 100	BERKELEY	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	001	3	2/15/2016	COMPETING CONTINUATION	$0
														Subtotal = $530,775

Grand Total All Awards = $668,603

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Developing small molecule inhibitors of TLR8 for treatment of rheumatoid arthritis

Award Number: R44AI100376

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2012

PERIOD OF PERFORMANCE END DATE: 01/31/2018

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