Targeting cancer with small molecule pan-KRAS degraders

Johannes Popow; William Farnaby; Andreas Gollner; Christiane Kofink; Gerhard Fischer; Melanie Wurm; David Zollman; Andre Wijaya; Nikolai Mischerikow; Carina Hasenoehrl; Polina Prokofeva; Heribert Arnhof; Silvia Arce-Solano; Sammy Bell; Georg Boeck; Emelyne Diers; Aileen B. Frost; Jake Goodwin-Tindall; Jale Karolyi-Oezguer; Shakil Khan; Theresa Klawatsch; Manfred Koegl; Roland Kousek; Barbara Kratochvil; Katrin Kropatsch; Arnel A. Lauber; Ross McLennan; Sabine Olt; Daniel Peter; Oliver Petermann; Vanessa Roessler; Peggy Stolt-Bergner; Patrick Strack; Eva Strauss; Nicole Trainor; Vesna Vetma; Claire Whitworth; Siying Zhong; Jens Quant; Harald Weinstabl; Bernhard Kuster; Peter Ettmayer; Alessio Ciulli

doi:10.1126/science.adm8684

Targeting cancer with small molecule pan-KRAS degraders

Johannes Popow, William Farnaby, Andreas Gollner, Christiane Kofink, Gerhard Fischer, Melanie Wurm, David Zollman, Andre Wijaya, Nikolai Mischerikow, Carina Hasenoehrl, Polina Prokofeva, Heribert Arnhof, Silvia Arce-Solano, Sammy Bell, Georg Boeck, Emelyne Diers, Aileen B. Frost, Jake Goodwin-Tindall, Jale Karolyi-Oezguer, Shakil KhanTheresa Klawatsch, Manfred Koegl, Roland Kousek, Barbara Kratochvil, Katrin Kropatsch, Arnel A. Lauber, Ross McLennan, Sabine Olt, Daniel Peter, Oliver Petermann, Vanessa Roessler, Peggy Stolt-Bergner, Patrick Strack, Eva Strauss, Nicole Trainor, Vesna Vetma, Claire Whitworth, Siying Zhong, Jens Quant, Harald Weinstabl, Bernhard Kuster, Peter Ettmayer (Lead / Corresponding author), Alessio Ciulli (Lead / Corresponding author)

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Abstract

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

Original language	English
Pages (from-to)	1338-1347
Number of pages	10
Journal	Science
Volume	385
Issue number	6715
DOIs	https://doi.org/10.1126/science.adm8684
Publication status	Published - 20 Sept 2024

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Author accepted manuscriptAccepted author manuscript, 1.19 MBLicence: CC BY

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Popow, J., Farnaby, W., Gollner, A., Kofink, C., Fischer, G., Wurm, M., Zollman, D., Wijaya, A., Mischerikow, N., Hasenoehrl, C., Prokofeva, P., Arnhof, H., Arce-Solano, S., Bell, S., Boeck, G., Diers, E., Frost, A. B., Goodwin-Tindall, J., Karolyi-Oezguer, J., ... Ciulli, A. (2024). Targeting cancer with small molecule pan-KRAS degraders. Science, 385(6715), 1338-1347. https://doi.org/10.1126/science.adm8684

@article{72036bef3a574c69ad11454ea552c4ad,

title = "Targeting cancer with small molecule pan-KRAS degraders",

abstract = "Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.",

author = "Johannes Popow and William Farnaby and Andreas Gollner and Christiane Kofink and Gerhard Fischer and Melanie Wurm and David Zollman and Andre Wijaya and Nikolai Mischerikow and Carina Hasenoehrl and Polina Prokofeva and Heribert Arnhof and Silvia Arce-Solano and Sammy Bell and Georg Boeck and Emelyne Diers and Frost, {Aileen B.} and Jake Goodwin-Tindall and Jale Karolyi-Oezguer and Shakil Khan and Theresa Klawatsch and Manfred Koegl and Roland Kousek and Barbara Kratochvil and Katrin Kropatsch and Lauber, {Arnel A.} and Ross McLennan and Sabine Olt and Daniel Peter and Oliver Petermann and Vanessa Roessler and Peggy Stolt-Bergner and Patrick Strack and Eva Strauss and Nicole Trainor and Vesna Vetma and Claire Whitworth and Siying Zhong and Jens Quant and Harald Weinstabl and Bernhard Kuster and Peter Ettmayer and Alessio Ciulli",

year = "2024",

month = sep,

day = "20",

doi = "10.1126/science.adm8684",

language = "English",

volume = "385",

pages = "1338--1347",

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Popow, J, Farnaby, W, Gollner, A, Kofink, C, Fischer, G, Wurm, M, Zollman, D , Wijaya, A, Mischerikow, N, Hasenoehrl, C, Prokofeva, P, Arnhof, H, Arce-Solano, S, Bell, S, Boeck, G, Diers, E, Frost, AB, Goodwin-Tindall, J, Karolyi-Oezguer, J, Khan, S, Klawatsch, T, Koegl, M, Kousek, R, Kratochvil, B, Kropatsch, K, Lauber, AA, McLennan, R, Olt, S, Peter, D, Petermann, O, Roessler, V, Stolt-Bergner, P, Strack, P, Strauss, E, Trainor, N, Vetma, V, Whitworth, C, Zhong, S, Quant, J, Weinstabl, H, Kuster, B, Ettmayer, P & Ciulli, A 2024, 'Targeting cancer with small molecule pan-KRAS degraders', Science, vol. 385, no. 6715, pp. 1338-1347. https://doi.org/10.1126/science.adm8684

TY - JOUR

T1 - Targeting cancer with small molecule pan-KRAS degraders

AU - Popow, Johannes

AU - Farnaby, William

AU - Gollner, Andreas

AU - Kofink, Christiane

AU - Fischer, Gerhard

AU - Wurm, Melanie

AU - Zollman, David

AU - Wijaya, Andre

AU - Mischerikow, Nikolai

AU - Hasenoehrl, Carina

AU - Prokofeva, Polina

AU - Arnhof, Heribert

AU - Arce-Solano, Silvia

AU - Bell, Sammy

AU - Boeck, Georg

AU - Diers, Emelyne

AU - Frost, Aileen B.

AU - Goodwin-Tindall, Jake

AU - Karolyi-Oezguer, Jale

AU - Khan, Shakil

AU - Klawatsch, Theresa

AU - Koegl, Manfred

AU - Kousek, Roland

AU - Kratochvil, Barbara

AU - Kropatsch, Katrin

AU - Lauber, Arnel A.

AU - McLennan, Ross

AU - Olt, Sabine

AU - Peter, Daniel

AU - Petermann, Oliver

AU - Roessler, Vanessa

AU - Stolt-Bergner, Peggy

AU - Strack, Patrick

AU - Strauss, Eva

AU - Trainor, Nicole

AU - Vetma, Vesna

AU - Whitworth, Claire

AU - Zhong, Siying

AU - Quant, Jens

AU - Weinstabl, Harald

AU - Kuster, Bernhard

AU - Ettmayer, Peter

AU - Ciulli, Alessio

PY - 2024/9/20

Y1 - 2024/9/20

N2 - Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

AB - Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

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U2 - 10.1126/science.adm8684

DO - 10.1126/science.adm8684

M3 - Article

C2 - 39298590

SN - 0036-8075

VL - 385

SP - 1338

EP - 1347

JO - Science

JF - Science

IS - 6715

ER -

Targeting cancer with small molecule pan-KRAS degraders

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A Translational Engine for Biomedical Discoveries (Strategic Grant)

Strategic Award: Wellcome Trust Technology Platform

State-of-the-Art Facilities for Structural Biology at the University of Dundee

Crystal Structure of compound 4 in complex with KRAS G12V C118S GDP and pVHL:ElonginC:ElonginB