The Needle Issue #2
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Welcome to the latest issue of the Needle, a newsletter from Haystack Science on preclinical biotech. If you are interested in science commercialization and how to take your early-stage discovery to market, this newsletter is for you. We aim to provide quick and insightful updates on preclinical research and the business around it every week. If you find the content helpful, please forward it to your friends and colleagues. This week, we delve into CD36 as a receptor to help PROTACs cross the cell membrane — an insight that could be leveraged to improve the efficacy of PROTAC drugs. Elsewhere, the scramble of deals continues for multispecific antibodies and antibody-drug conjugates (ADCs) in cancer and autoimmune disease. Several initiatives are underway to counter the aftershocks of sweeping cuts at the FDA and NIH as they ripple down to startups.
Haystack chat Over 25 proteolysis-targeting chimeras (PROTACs) are in the clinic with many more in preclinical development. AACR this week features >60 abstracts on PROTAC drugs against lung, prostate, breast, ovarian, colorectal and pancreatic cancers as well as lymphomas and leukemias. Often assumed to cross the membrane through passive diffusion, the actual mechanism whereby PROTACs enter cells isn’t fully understood, especially given their bulky size (>800 Da) compared with traditional drugs (300-500 Da). Now, several groups led by Hong-Yu Li and colleagues, of the University of Texas Health Science Center and the University of Arkansas for Medical Sciences, have obtained compelling evidence that CD36-mediated endocytosis is responsible for PROTAC internalization. Using a PROTAC-like biotinylated probe to identify interacting membrane proteins, the team pinpointed CD36 as the transporter. Reducing protein levels via RNA interference in prostate- and breast-cancer cell lines resulted in decreased PROTAC-mediated target proteolysis and cytotoxicity, an effect that depended on two proteins (EEA1 and Rab5) associated with endocytosis. The CD36 pathway also appears capable of mediating internalization for a diverse array of PROTACs with very different chemical structures, indicating that this is a general uptake pathway. With some clever medicinal chemistry, Li and colleagues modified existing PROTACs, including Arivinas’ androgen receptor targeting PROTAC bavdeglutamide, to optimize CD36 binding. These second-generation molecules, designed to act as prodrugs, show increased efficacy against tumors in mouse models compared with the parent molecules, presumably due to increased uptake. The results are notable given the underwhelming results recently reported for first-generation PROTACs compared with existing standard of care. In March, Pfizer/Arivinas announced that vepdegestrant, their PROTAC drug targeting estrogen receptor α, missed primary endpoints in ER⁺/HER2⁻ advanced breast cancer patients. Similarly, C4 Therapeutics’ BRD9 degrader failed to show sufficient efficacy in synovial sarcoma patients. Identifying CD36 as a central uptake pathway for PROTAC molecules could provide an approach to improve PROTAC cellular uptake and therefore ramp up potency. The authors suggest an important assay for PROTAC drug hunters would be “a cellular fluorescence resonance energy transfer (FRET) assay labeling CD36 and another protein in the cascade complex to allow direct, accurate, and effective measurement of CD36-mediated endocytic efficacy”. Several questions remain unresolved in the paper: As CD36 is a fatty acid transporter (for long-chain fatty acids and fat-soluble vitamins) and a scavenger receptor (taking up oxidized LDL, thrombospondin 1, and collagen), a big unknown is whether PROTAC uptake leads to activation of CD36 signaling pathways (via SFK, MAPK and NOX). If so, this could result in inflammation and even thrombosis. Similarly, we wonder whether higher levels of CD36 in human intestine, skin, lung, eye, muscle, mammary epithelium or spleen could make these tissue sinks for PROTAC molecules. Although CD36 is high in differentiated blood cells (platelets, erythrocytes and monocytes/macrophages), low expression in blood stem cells may explain why hematologic toxicity has not been seen for PROTACs unlike traditional cancer drugs. Papers: Best of the rest Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential | PNAS Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation | Nature Goings on Seed funding for therapeutics startups reverts to levels unseen for a decade Infinity Bio launches service for profiling mouse proteome against antibodies Biolabs at University of Vermont kicks off educational series to help founders perfect their pitch American Academy of Ophthalmology’s Eyecelerator highlights 37 startups presenting on May 5 LSX World Congress in London for accelerating European life science startups Preclinical funding
Preclinical deals
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If you’re interested in commercializing your science, get in touch. We can help you figure out the next steps for your startup’s translational research program and connect you with the right investor. Follow us on X, BlueSky and LinkedIn. Please send feedback; we’d love to hear from you (info@haystacksci.com). Until next week, Juan Carlos and Andy |