# MD-PHAR Controlling sphingosine 1-phosphate synthesis and trafficking

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $90,940

## Abstract

Sphingosine kinases (SphK1, SphK2) catalyze the formation of an important extracellular mediator,
sphingosine 1-phosphate (S1P). A fundamental aspect of S1P biology is the large difference in S1P
abundance between blood or lymph (high) and tissue (low), which is termed the S1P vascular gradient. This
gradient maintains vascular endothelial barrier function and facilitates lymphocyte mobilization from lymphoid
tissues. Indeed, S1P1 receptor agonist drugs (e.g. fingolimod) are therapeutically beneficial because S1P
signaling is highly sensitive to changes in S1P gradient. We used our SphK2 inhibitors to demonstrate that
interdicting S1P signaling at the level of synthesis steepens the S1P vascular gradient by slowing S1P
clearance from the blood. This result suggests that SphK2 inhibitors will be extremely useful in treating
conditions where the endothelial barrier is compromised, e.g. acute kidney injury and sepsis. Although our
recently discovered SphK2 inhibitors are active in vivo, improvements in potency, oral availability and chemical
diversity are needed to advance them to the clinic. We will accomplish these goals by generating additional
inhibitors on our current chemical scaffold and by developing a novel second scaffold. The current scaffold
has also yielded a few SphK1 inhibitors but these lack potency at mouse SphK1, which precludes their testing
for efficacy in some key disease models. In contrast to SphK2, inhibition of Sphk1 decreases the S1P vascular
gradient and to probe the resulting physiological consequences, multiple inhibitors are needed. We will use
iterative rounds of synthesis and testing to generate a library of SphK1 inhibitors with emphases on increasing
their potency at mouse SphK1 and discovering inhibitors that have suitable pharmacokinetic properties in
rodents. To understand the molecular mechanism of SphK inhibition as well as to inform the synthetic
chemistry strategies, we will solve the structures of both isozymes with bound inhibitors using X-ray
crystallography. Finally, we will discover a blocker of the S1P exporter, SPNS2, which provides the S1P to
lymph and thereby maintains the S1P vascular gradient that is required for lymphocyte egress from lymphoid
organs to lymph. Currently, due to the unavailability of SPNS2 inhibitors, this particular approach to the
manipulation of S1P gradient and subsequent immunomodulation remains completely unexplored. The
strength of our program is the synergism in the combination of chemistry (Santos) and pharmacology (Lynch)
to which we now add structural biology (Faham). Our central theme of is to understand the therapeutic
potential of manipulating the S1P gradients either at the level of synthesis (SphK inhibition) or transport
(SPNS2 blockade). We have a track record of productivity that enabled a fundamental insight into S1P
biology, e.g. our discovery that SphK2 inhibition modulates S1P signaling to protect endothelial function, a new
therapeutic strategy. Now, we prop...

## Key facts

- **NIH application ID:** 10157761
- **Project number:** 3R01GM121075-04S1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** KEVIN R. LYNCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $90,940
- **Award type:** 3
- **Project period:** 2016-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10157761

## Citation

> US National Institutes of Health, RePORTER application 10157761, MD-PHAR Controlling sphingosine 1-phosphate synthesis and trafficking (3R01GM121075-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10157761. Licensed CC0.

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