Adam Sperling, MD, PhD

All Publications

• Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation. Molecular cell Słabicki, M., Park, J., Nowak, R. P., Roy Burman, S. S., Pellman, J., Zou, C., Razumkov, H., Carreiro, J., Rastogi, S., Goldstein, A., Nagiec, M. M., Donovan, K. A., Che, J., Hunkeler, M., Geng, Q., Hsu, C. L., Lakshminarayan, M., Shu, C., Zon, R. L., Kozicka, Z., Park, P. M., Tsai, J. M., Yoon, H., Jones, L. H., Sperling, A. S., Gray, N. S., Fischer, E. S., Ebert, B. L. 2025; 85 (16): 3184-3201.e14

  Abstract

  Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4CRBN to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has been characterized, it does not fully explain substrate specificity. To explore the role of residues adjacent to this core motif, we constructed a comprehensive ZF reporter library of 9,097 reporters derived from 1,655 human ZF proteins and conducted a library-on-library screen with 29 glutarimide analogs to identify compounds that collectively degrade 38 ZF reporters. Cryo-electron microscopy and crystal structures of ZFs in complex with CRBN revealed the importance of interactions beyond the core ZF degron. We used systematic mutagenesis of ZFs and CRBN to identify modes of neosubstrate recruitment requiring distinct amino acids. Finally, we found subtle chemical variations in glutarimide analogs that alter target scope and selectivity, thus providing a roadmap for their rational design.

  View details for DOI 10.1016/j.molcel.2025.07.019

  View details for PubMedID 40845806

• Real-World Experience with Teclistamab for Relapsed/ Refractory Multiple Myeloma from the U.S. Myeloma Immunotherapy Consortium. Blood cancer discovery Razzo, B. M., Midha, S., Portuguese, A. J., Grajales-Cruz, A. F., De Menezes Silva Corraes, A., Costello, P., Liu, Y., Sperling, A. S., Nadeem, O., Dima, D., Banerjee, R., Cowan, A. J., Afrough, A., Anderson, L. D., Lieberman-Cribbin, A., Kaur, G., Goyal, A., Atrash, S., Ferreri, C. J., Voorhees, P. M., Pasvolsky, O., Lee, H. C., Patel, K. K., Julian, K. L., Forsberg, P. A., Herr, M. M., Chhabra, S., Parrondo, R. D., Lin, Y., Chen, A., Susanibar-Adaniya, S. P., Khouri, J., Raza, S., Anwer, F., Vazquez-Martinez, M., Castaneda Puglianini, O., Sborov, D. W., Davis, J. A., Rossi, A., Shune, L., Bhurtel, J., Hwang, W. T., Hansen, D. K., Sidana, S., Garfall, A. L., Richard, S. 2025

  Abstract

  Teclistamab is an anti-CD3xBCMA bispecific antibody approved for use in relapsed/refractory multiple myeloma (MM). We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the U.S. MM Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≥3) with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR (VGPR) or better in 45%. With 10.1 months median follow-up, estimated median progression-free survival (PFS) was 5.8 months, and 12-month overall survival was 61%. Independent predictors of

  View details for DOI 10.1158/2643-3230.BCD-24-0354

  View details for PubMedID 40629516

• Development of PDE6D and CK1alpha Degraders through Chemical Derivatization of FPFT-2216. Journal of medicinal chemistry Teng, M., Lu, W., Donovan, K. A., Sun, J., Krupnick, N. M., Nowak, R. P., Li, Y., Sperling, A. S., Zhang, T., Ebert, B. L., Fischer, E. S., Gray, N. S. 1800

  Abstract

  Immunomodulatory drugs are a class of drugs approved for the treatment of multiple myeloma. These compounds exert their clinical effects by inducing interactions between the CRL4CRBN E3 ubiquitin ligase and a C2H2 zinc finger degron motif, resulting in degradation of degron-containing targets. However, although many cellular proteins feature the degron motif, only a subset of those are degradable via this strategy. Here, we demonstrated that FPFT-2216, a previously reported "molecular glue" compound, degrades PDE6D, in addition to IKZF1, IKZF3, and CK1alpha. We used FPFT-2216 as a starting point for a focused medicinal chemistry campaign and developed TMX-4100 and TMX-4116, which exhibit greater selectivity for degrading PDE6D and CK1alpha, respectively. We also showed that the region in PDE6D that interacts with the FPFT-2216 derivatives is not the previously pursued prenyl-binding pocket. Moreover, we found that PDE6D depletion by FPFT-2216 does not impede the growth of KRASG12C-dependent MIA PaCa-2 cells, highlighting the challenges of drugging PDE6D-KRAS. Taken together, the approach we described here represents a general scheme to rapidly develop selective degraders by reprogramming E3 ubiquitin ligase substrate specificity.

  View details for DOI 10.1021/acs.jmedchem.1c01832

  View details for PubMedID 34965125

• Association of Clonal Hematopoiesis with Chronic Obstructive Pulmonary Disease. Blood Miller, P., Qiao, D., Rojas-Quintero, J., Honigberg, M. C., Sperling, A. S., Gibson, C. J., Bick, A. G., Niroula, A., McConkey, M. E., Sandoval, B., Miller, B., Shi, W., Viswanathan, K., Leventhal, M. J., Werner, L., Moll, M., Cade, B., Barr, R. G., Correa, A., Cupples, L. A., Gharib, S. A., Jain, D., Gogarten, S., Lange, L., London, S., Manichaikul, A., O'Connor, G., Oelsner, E., Redline, S., Rich, S. S., Rotter, J. I., Ramachandran, V., Yu, B., Sholl, L. M., Neuberg, D., Jaiswal, S., Levy, B., Owen, C., Natarajan, P., Silverman, E. K., van Galen, P., Tesfaigzi, Y., Cho, M., Ebert, B. L. 2021

  Abstract

  Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association with COPD remains unclear. We analyzed whole-genome and exome sequencing data to detect CHIP in 48,835 subjects, of whom 8,444 had moderate-to-very-severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In COPDGene, individuals with CHIP had a risk of moderate-to-severe and severe or very severe COPD 1.6 and 2.2 times greater than non-carriers, respectively (adjusted 95% confidence intervals [CI], 1.1 to 2.2 and 1.5 to 3.2). These findings were consistent observed in three additional cohorts and meta-analyses of all subjects. CHIP was also associated with decreased FEV1% predicted in COPDGene (mean between group difference -5.7%; adjusted 95% CI, -8.8 to -2.6), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (OR 1.03 per ten pack-years, 95% CI 1.01-1.05) in the meta-analysis of all subjects. Inactivation of Tet2 in mouse hematopoietic cells exacerbated emphysema development and inflammation in cigarette smoke exposure models. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.

  View details for DOI 10.1182/blood.2021013531

  View details for PubMedID 34855941

• Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy. American journal of hematology Garcia, J. S., Bhatt, S., Fell, G., Sperling, A. S., Burgess, M., Keshishian, H., Yilma, B., Brunner, A., Neuberg, D., Carr, S. A., Ebert, B. L., Ballen, K., Stone, R. M., DeAngelo, D. J., Medeiros, B. C., Letai, A. 2019

  Abstract

  Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials testing the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts and found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ajh.25692

  View details for PubMedID 31804723

• The Drosophila BRM complex facilitates global transcription by RNA polymerase II EMBO JOURNAL Armstrong, J. A., Papoulas, O., Daubresse, G., Sperling, A. S., Lis, J. T., Scott, M. P., Tamkun, J. W. 2002; 21 (19): 5245-5254

  Abstract

  Drosophila brahma (brm) encodes the ATPase subunit of a 2 MDa complex that is related to yeast SWI/SNF and other chromatin-remodeling complexes. BRM was identified as a transcriptional activator of Hox genes required for the specification of body segment identities. To clarify the role of the BRM complex in the transcription of other genes, we examined its distribution on larval salivary gland polytene chromosomes. The BRM complex is associated with nearly all transcriptionally active chromatin in a pattern that is generally non-overlapping with that of Polycomb, a repressor of Hox gene transcription. Reduction of BRM function dramatically reduces the association of RNA polymerase II with salivary gland chromosomes. A few genes, such as induced heat shock loci, are not associated with the BRM complex; transcription of these genes is not compromised by loss of BRM function. The distribution of the BRM complex thus correlates with a dependence on BRM for gene activity. These data suggest that the chromatin remodeling activity of the BRM complex plays a general role in facilitating transcription by RNA polymerase II.

  View details for Web of Science ID 000178502600024

  View details for PubMedID 12356740

  View details for PubMedCentralID PMC129039